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Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4.
Science. 2011 Apr 29; 332(6029):600-3
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09 May 2011
New Finding
DOI: 10.3410/f.10227956.11018054
This report surprisingly identifies a new extrinsic mechanism by which cytotoxic T lymphocyte antigen (CTLA)-4 inhibits CD28 costimulation.
The starting point of this study was the observation of: 1) the highly endocytic behaviour of CTLA-4; and 2) a probable extrinsic function of this receptor (see...Continue reading
The starting point of this study was the observation of: 1) the highly endocytic behaviour of CTLA-4; and 2) a probable extrinsic function of this receptor (see...Continue reading
This report surprisingly identifies a new extrinsic mechanism by which cytotoxic T lymphocyte antigen (CTLA)-4 inhibits CD28 costimulation.
The starting point of this study was the observation of: 1) the highly endocytic behaviour of CTLA-4; and 2) a probable extrinsic function of this receptor (see {1,2} below).
The authors reveal a mechanism of trans-endocytosis of CD80 and CD86 ligands, which operates in an antigen-dependent manner in vivo and probably involves both activated and regulatory T cells expressing CTLA-4.
The authors first culture cells expressing CTLA-4 with cells expressing a C-terminally tagged CD86 protein and they report a substantial transfer of CD86 into CTLA-4+ cells. Over 50% of CTLA-4+ cells acquire ligand within 3hrs.
They document this finding by showing that, in the presence of activated T cells, human dendritic cells display reduced CD86 on the plasma membrane and display a punctuate pattern that co-localizes with CTLA-4.
Finally, they develop an in vivo model in the mouse and show that 25-40% of CD4+ CD25+ T cells acquire CD86-green fluorescent protein (GFP) expressed by dendritic cells.
Among others, these two articles by Friedline et al. {1} and Schmidt et al. {2} have shown that CTLA-4 can act in trans to maintain self-tolerance, suggesting a cell-extrinsic function for CTLA-4.
The starting point of this study was the observation of: 1) the highly endocytic behaviour of CTLA-4; and 2) a probable extrinsic function of this receptor (see {1,2} below).
The authors reveal a mechanism of trans-endocytosis of CD80 and CD86 ligands, which operates in an antigen-dependent manner in vivo and probably involves both activated and regulatory T cells expressing CTLA-4.
The authors first culture cells expressing CTLA-4 with cells expressing a C-terminally tagged CD86 protein and they report a substantial transfer of CD86 into CTLA-4+ cells. Over 50% of CTLA-4+ cells acquire ligand within 3hrs.
They document this finding by showing that, in the presence of activated T cells, human dendritic cells display reduced CD86 on the plasma membrane and display a punctuate pattern that co-localizes with CTLA-4.
Finally, they develop an in vivo model in the mouse and show that 25-40% of CD4+ CD25+ T cells acquire CD86-green fluorescent protein (GFP) expressed by dendritic cells.
Among others, these two articles by Friedline et al. {1} and Schmidt et al. {2} have shown that CTLA-4 can act in trans to maintain self-tolerance, suggesting a cell-extrinsic function for CTLA-4.
References
1.
CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance.
J Exp Med 2009 Feb 16; 2(206):421-34
PMID: 19188497
2.
Ctla-4 controls regulatory T cell peripheral homeostasis and is required for suppression of pancreatic islet autoimmunity.
J Immunol 2009 Jan 1; 1(182):274-82
PMID: 19109158
Disclosures
None declared
Add Comment
Moser M and Leo O: F1000Prime Recommendation of [Qureshi OS et al., Science 2011, 332(6029):600-3]. In F1000Prime, 09 May 2011; DOI: 10.3410/f.10227956.11018054. F1000Prime.com/10227956#eval11018054
10 May 2011
New Finding
DOI: 10.3410/f.10227956.11091054
This study represents a significant breakthrough in our understanding of the mechanistic basis of the well-established inhibitory function of cytotoxic T lymphocyte antigen 4 (CTLA-4), a T cell receptor that inhibits T cell responses and prevents autoimmunity, by providing convincing evidence that C4...Continue reading
This study represents a significant breakthrough in our understanding of the mechanistic basis of the well-established inhibitory function of cytotoxic T lymphocyte antigen 4 (CTLA-4), a T cell receptor that inhibits T cell responses and prevents autoimmunity, by providing convincing evidence that CTLA-4 functions in a cell-extrinsic manner to capture and deplete its ligands, CD80 and CD86, from antigen-presenting cells (APCs), resulting in impaired costimulatory function via T cell-expressed CD28.
The mechanism that underlies the negative immunoregulatory function of CTLA-4 has been debated for a long time, and both T cell-intrinsic and -extrinsic pathways of inhibition have been demonstrated. The authors have used several imaging techniques and functional T cell stimulation assays to demonstrate that CTLA-4 expressed on effector and regulatory T cells unidirectionally captures and removes its ligands from neighboring cells, leading to trans-endocytosis and degradation of CD80 and CD86 within the CTLA-4+ cell. As a result, expression of these ligands on APCs is greatly decreased and, therefore, their ability to costimulate CD28-dependent T cell activation and proliferation is impaired. The authors further demonstrate that this inhibitory function depends on CTLA-4 endocytosis. Importantly, the authors provide evidence that this novel mechanism also operates in an in vivo setting and, furthermore, that in contrast to CTLA-4, CD28 is incapable of capturing and trans-endocytosing CD80 and CD86. These findings provide a neat explanation for the apparent paradox that despite binding the same ligands (CD80 and CD86), CD28 and its relative, CTLA-4, have opposing effects on T cell activation and proliferation, and will surely open the way to new and promising studies on the function and regulation of CTLA-4 in normal and pathological immune responses, especially autoimmune diseases and tumor immunity.
The mechanism that underlies the negative immunoregulatory function of CTLA-4 has been debated for a long time, and both T cell-intrinsic and -extrinsic pathways of inhibition have been demonstrated. The authors have used several imaging techniques and functional T cell stimulation assays to demonstrate that CTLA-4 expressed on effector and regulatory T cells unidirectionally captures and removes its ligands from neighboring cells, leading to trans-endocytosis and degradation of CD80 and CD86 within the CTLA-4+ cell. As a result, expression of these ligands on APCs is greatly decreased and, therefore, their ability to costimulate CD28-dependent T cell activation and proliferation is impaired. The authors further demonstrate that this inhibitory function depends on CTLA-4 endocytosis. Importantly, the authors provide evidence that this novel mechanism also operates in an in vivo setting and, furthermore, that in contrast to CTLA-4, CD28 is incapable of capturing and trans-endocytosing CD80 and CD86. These findings provide a neat explanation for the apparent paradox that despite binding the same ligands (CD80 and CD86), CD28 and its relative, CTLA-4, have opposing effects on T cell activation and proliferation, and will surely open the way to new and promising studies on the function and regulation of CTLA-4 in normal and pathological immune responses, especially autoimmune diseases and tumor immunity.
Disclosures
None declared
Altman A: F1000Prime Recommendation of [Qureshi OS et al., Science 2011, 332(6029):600-3]. In F1000Prime, 10 May 2011; DOI: 10.3410/f.10227956.11091054. F1000Prime.com/10227956#eval11091054
10 May 2011
New Finding
DOI: 10.3410/f.10227956.11038055
This study shows that cytotoxic T lymphocyte antigen (CTLA)-4 on activated T cells can 'catch' its ligand CD86/CD80 and perform a 'trans-endocytosis' as a way to remove these ligands from antigen-presenting cells (APCs).
This finding adds, as the third major mechanism, to an explanation of the suppression...Continue reading
This finding adds, as the third major mechanism, to an explanation of the suppression...Continue reading
This study shows that cytotoxic T lymphocyte antigen (CTLA)-4 on activated T cells can 'catch' its ligand CD86/CD80 and perform a 'trans-endocytosis' as a way to remove these ligands from antigen-presenting cells (APCs).
This finding adds, as the third major mechanism, to an explanation of the suppression of T cell responses by CTLA-4, in addition to: 1) transmission of negative signals to CTLA-4 after its interaction with the ligands and: 2) reverse signaling by CD80/CD86 into APCs to induce suppressive indoleamine 2,3-dioxygenase (IDO).
This finding adds, as the third major mechanism, to an explanation of the suppression of T cell responses by CTLA-4, in addition to: 1) transmission of negative signals to CTLA-4 after its interaction with the ligands and: 2) reverse signaling by CD80/CD86 into APCs to induce suppressive indoleamine 2,3-dioxygenase (IDO).
Disclosures
None declared
Chen L: F1000Prime Recommendation of [Qureshi OS et al., Science 2011, 332(6029):600-3]. In F1000Prime, 10 May 2011; DOI: 10.3410/f.10227956.11038055. F1000Prime.com/10227956#eval11038055
12 May 2011
DOI: 10.3410/f.10227956.11055058
This article interestingly demonstrates that T cells, including regulatory T cells (Tregs), pluck CD80/CD86 molecules from antigen-presenting cells (APCs) after their engagement with cytotoxic T lymphocyte antigen 4 (CTLA-4), resulting in the decreased costimulatory potency of APCs.
The suppression of...Continue reading
The suppression of...Continue reading
This article interestingly demonstrates that T cells, including regulatory T cells (Tregs), pluck CD80/CD86 molecules from antigen-presenting cells (APCs) after their engagement with cytotoxic T lymphocyte antigen 4 (CTLA-4), resulting in the decreased costimulatory potency of APCs.
The suppression of a molecular function can be transient or sustained. The inhibitory effect of Tregs on APCs may include not only the blocking of the binding of CD80/CD86 to co-stimulatory CD28, but also the plucking of CD80/CD86 with surrounding membrane lipid fraction by CTLA-4. This phenomenon resembles the effect of an anti-tumor necrosis factor (TNF) antibody, such as infliximab, which induces apoptosis of TNF-producing macrophages in addition to the neutralization of TNF {1}. The molecular complex of CD80/CD86 and CTLA-4 is then transferred to the vesicles in the CTLA-4-expressing T cells. The subsequent fate of CTLA-4 and CD80/CD86 may be different: CTLA-4 is likely to be recycled to the plasma membrane, while CD80/CD86 has been shown to be degradated in lysosomes. This trans-endocytosis of CD80/86 via CTLA-4 has been observed even in resting T cells with an upregulation in activated T cells. Soluble CTLA-4 does not seem to downregulate the CD80/CD86 expression on APCs because the addition of CTLA4-Ig inhibited the trans-endocytosis of CD80/CD86. The strength of this article is the abundance of in vitro and in vivo data including beautiful video images. Future directions may be the elucidation of the sorting difference between CTLA-4 and CD80/CD86, sustainability of the downregulated expression of CD80/CD86 and the clinical significance of their findings.
The suppression of a molecular function can be transient or sustained. The inhibitory effect of Tregs on APCs may include not only the blocking of the binding of CD80/CD86 to co-stimulatory CD28, but also the plucking of CD80/CD86 with surrounding membrane lipid fraction by CTLA-4. This phenomenon resembles the effect of an anti-tumor necrosis factor (TNF) antibody, such as infliximab, which induces apoptosis of TNF-producing macrophages in addition to the neutralization of TNF {1}. The molecular complex of CD80/CD86 and CTLA-4 is then transferred to the vesicles in the CTLA-4-expressing T cells. The subsequent fate of CTLA-4 and CD80/CD86 may be different: CTLA-4 is likely to be recycled to the plasma membrane, while CD80/CD86 has been shown to be degradated in lysosomes. This trans-endocytosis of CD80/86 via CTLA-4 has been observed even in resting T cells with an upregulation in activated T cells. Soluble CTLA-4 does not seem to downregulate the CD80/CD86 expression on APCs because the addition of CTLA4-Ig inhibited the trans-endocytosis of CD80/CD86. The strength of this article is the abundance of in vitro and in vivo data including beautiful video images. Future directions may be the elucidation of the sorting difference between CTLA-4 and CD80/CD86, sustainability of the downregulated expression of CD80/CD86 and the clinical significance of their findings.
References
1.
Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents.
Rheumatology (Oxford) 2010 Jul; 7(49):1215-28
PMID: 20194223
Disclosures
None declared
Takeuchi T and Kameda H: F1000Prime Recommendation of [Qureshi OS et al., Science 2011, 332(6029):600-3]. In F1000Prime, 12 May 2011; DOI: 10.3410/f.10227956.11055058. F1000Prime.com/10227956#eval11055058
19 May 2011
New Finding
DOI: 10.3410/f.10227956.11502054
This is an exciting study because it describes a novel mechanism by which cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibits T cell-mediated responses.
The authors show that T cells internalize the costimulatory molecule CD86 on antigen-presenting cells (APCs) using CTLA-4 in a process the authors...Continue reading
The authors show that T cells internalize the costimulatory molecule CD86 on antigen-presenting cells (APCs) using CTLA-4 in a process the authors...Continue reading
This is an exciting study because it describes a novel mechanism by which cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibits T cell-mediated responses.
The authors show that T cells internalize the costimulatory molecule CD86 on antigen-presenting cells (APCs) using CTLA-4 in a process the authors refer to as 'trans-endocytosis'. These results explain many interesting facets of the biology of CTLA-4, including the endosomal location of the molecule and the higher affinity of CTLA-4 for CD80/CD86 compared to CD28. The authors provide compelling evidence that this process occurs in vivo, in an antigen specific manner. This means that T cells can regulate the costimulatory functions of selected populations of APCs.
The authors show that T cells internalize the costimulatory molecule CD86 on antigen-presenting cells (APCs) using CTLA-4 in a process the authors refer to as 'trans-endocytosis'. These results explain many interesting facets of the biology of CTLA-4, including the endosomal location of the molecule and the higher affinity of CTLA-4 for CD80/CD86 compared to CD28. The authors provide compelling evidence that this process occurs in vivo, in an antigen specific manner. This means that T cells can regulate the costimulatory functions of selected populations of APCs.
Disclosures
None declared
Wucherpfennig K: F1000Prime Recommendation of [Qureshi OS et al., Science 2011, 332(6029):600-3]. In F1000Prime, 19 May 2011; DOI: 10.3410/f.10227956.11502054. F1000Prime.com/10227956#eval11502054
24 May 2011
New Finding
DOI: 10.3410/f.10227956.11628055
We have known for some time that cytotoxic T lymphocyte antigen-4 (CTLA-4; cluster of differentiation 152 [CD152]) has a cell intrinsic, negative signalling role on anergic and regulatory T cells; but, until now, we have been unable to explain how CTLA-4 is involved in the extrinsic regulation of immune...Continue reading
We have known for some time that cytotoxic T lymphocyte antigen-4 (CTLA-4; cluster of differentiation 152 [CD152]) has a cell intrinsic, negative signalling role on anergic and regulatory T cells; but, until now, we have been unable to explain how CTLA-4 is involved in the extrinsic regulation of immune responses. This paper demonstrates for the first time that CTLA-4 effectively grabs the co-stimulatory ligands CD80 and CD86 and rips them off the surface of antigen-presenting cells.
A process of trans-endocytosis by the CTLA-4-expressing T cell then internalizes and degrades the complexes. The outcome is that the antigen-presenting cells can no longer provide effective co-stimulatory ligands for CD28 and are, therefore, compromised in their ability to activate effector T cell differentiation. Interestingly, this paper shows that although regulatory T cells perform this trans-endocytosis of CTLA-4/CD86 complexes constitutively it is more rapid after T cell receptor (TCR) stimulation, which is known to be important for activating the suppressive function of regulatory T cells. Trans-endocytosis of CTLA-4/CD86 was also seen to occur in activated effector cells during the period when they transiently express CTLA-4. This suggests that this mechanism is also involved in the normal process that limits or terminates the immune effector cell response.
A process of trans-endocytosis by the CTLA-4-expressing T cell then internalizes and degrades the complexes. The outcome is that the antigen-presenting cells can no longer provide effective co-stimulatory ligands for CD28 and are, therefore, compromised in their ability to activate effector T cell differentiation. Interestingly, this paper shows that although regulatory T cells perform this trans-endocytosis of CTLA-4/CD86 complexes constitutively it is more rapid after T cell receptor (TCR) stimulation, which is known to be important for activating the suppressive function of regulatory T cells. Trans-endocytosis of CTLA-4/CD86 was also seen to occur in activated effector cells during the period when they transiently express CTLA-4. This suggests that this mechanism is also involved in the normal process that limits or terminates the immune effector cell response.
Disclosures
None declared
Cobbold S: F1000Prime Recommendation of [Qureshi OS et al., Science 2011, 332(6029):600-3]. In F1000Prime, 24 May 2011; DOI: 10.3410/f.10227956.11628055. F1000Prime.com/10227956#eval11628055
27 May 2011
New Finding
DOI: 10.3410/f.10227956.11688055
The cell-extrinsic suppressive function of cytotoxic T lymphocyte antigen-4 (CTLA-4) has been described for some time {1}, but the mechanism involved remained unclear. This study provides the first molecular explanation for this phenomenon.
Using co-cultures of Chinese hamster ovary (CHO) cells expressing...Continue reading
Using co-cultures of Chinese hamster ovary (CHO) cells expressing...Continue reading
The cell-extrinsic suppressive function of cytotoxic T lymphocyte antigen-4 (CTLA-4) has been described for some time {1}, but the mechanism involved remained unclear. This study provides the first molecular explanation for this phenomenon.
Using co-cultures of Chinese hamster ovary (CHO) cells expressing either CTLA-4 or cluster of differentiation 86 (CD86), the authors observed the transfer of CD86 to intracellular vesicles in CTLA-4+ cells, a process termed trans-endocytosis. The subsequent diminution in CD86 levels resulted in impaired co-stimulatory capacities of CD86-expressing CHO cells.
The authors obtained similar results with human activated T cells and monocyte-derived DCs, as well as with resting T cells transfected with CTLA-4 or with regulatory T cells that constitutively expressed CTLA-4. Furthermore, the process appeared specific to CTLA-4 and CD80/86, as it could be blocked by antibodies directed against CTLA-4 but not CD28, and as the levels of other surface molecules including CD40 or human leukocyte antigen-D-related (HLA9-DR) were unaffected. Furthermore, they demonstrated that this trans-endocytosis can occur in vivo in mice, and showed acquisition of CD86 by both regulatory and activated T cells.
Altogether, this study describes a new, cell-extrinsic, mechanism for CTLA-4-mediated inhibition through diminution of CD86 levels on antigen-presenting cells. Examining the relative contribution of this phenomenon to the regulation of immune responses and homeostasis in vivo should open new avenues for studying CTLA-4 function.
Using co-cultures of Chinese hamster ovary (CHO) cells expressing either CTLA-4 or cluster of differentiation 86 (CD86), the authors observed the transfer of CD86 to intracellular vesicles in CTLA-4+ cells, a process termed trans-endocytosis. The subsequent diminution in CD86 levels resulted in impaired co-stimulatory capacities of CD86-expressing CHO cells.
The authors obtained similar results with human activated T cells and monocyte-derived DCs, as well as with resting T cells transfected with CTLA-4 or with regulatory T cells that constitutively expressed CTLA-4. Furthermore, the process appeared specific to CTLA-4 and CD80/86, as it could be blocked by antibodies directed against CTLA-4 but not CD28, and as the levels of other surface molecules including CD40 or human leukocyte antigen-D-related (HLA9-DR) were unaffected. Furthermore, they demonstrated that this trans-endocytosis can occur in vivo in mice, and showed acquisition of CD86 by both regulatory and activated T cells.
Altogether, this study describes a new, cell-extrinsic, mechanism for CTLA-4-mediated inhibition through diminution of CD86 levels on antigen-presenting cells. Examining the relative contribution of this phenomenon to the regulation of immune responses and homeostasis in vivo should open new avenues for studying CTLA-4 function.
References
1.
Cutting edge: lymphoproliferative disease in the absence of CTLA-4 is not T cell autonomous.
J Immunol 1999 Aug 1; 3(163):1128-31
PMID: 10415006
Disclosures
None declared
Bousso P and Deguine J: F1000Prime Recommendation of [Qureshi OS et al., Science 2011, 332(6029):600-3]. In F1000Prime, 27 May 2011; DOI: 10.3410/f.10227956.11688055. F1000Prime.com/10227956#eval11688055
31 May 2011
New Finding
DOI: 10.3410/f.10227956.11733054
This paper is of considerable importance because it provides an explanation of the cell extrinsic mechanism of cytotoxic T lymphocyte antigen-4 (CTLA-4). This receptor has long been considered a co-inhibitory receptor, which works by giving a negative signal to T cells, but the mechanism via which it...Continue reading
This paper is of considerable importance because it provides an explanation of the cell extrinsic mechanism of cytotoxic T lymphocyte antigen-4 (CTLA-4). This receptor has long been considered a co-inhibitory receptor, which works by giving a negative signal to T cells, but the mechanism via which it downregulates CD80 (cluster of differentiation 80) and CD86 was unknown. This study provides an explanation of how CTLA-4 works in an extrinsic manner, but certainly does not exclude other intrinsic mechanisms that may yet be found. The existence of intrinsic mechanisms is suggested by variant forms of CTLA-4 that do not bind ligands, but still have immunoregulatory activity.
The authors demonstrate that once CTLA-4 binds to CD80/86, this complex is internalized and CD80/86 are degraded. Thus, the end result is less CD80/86 on the cell surface to provide the second signal for T cell activation. CTLA-4 is important with respect to control of autoimmunity and immune homeostasis and this study helps in our understanding of how this immunoregulation works.
The authors demonstrate that once CTLA-4 binds to CD80/86, this complex is internalized and CD80/86 are degraded. Thus, the end result is less CD80/86 on the cell surface to provide the second signal for T cell activation. CTLA-4 is important with respect to control of autoimmunity and immune homeostasis and this study helps in our understanding of how this immunoregulation works.
Disclosures
None declared
Conrad D: F1000Prime Recommendation of [Qureshi OS et al., Science 2011, 332(6029):600-3]. In F1000Prime, 31 May 2011; DOI: 10.3410/f.10227956.11733054. F1000Prime.com/10227956#eval11733054
01 Jun 2011
New Finding
DOI: 10.3410/f.10227956.11768055
This article describes a novel mechanism for the function of cytotoxic T lymphocyte antigen 4 (CTLA-4) in negative regulation of T cell activation.
CD28-mediated co-stimulation is critical for the regulation of T cell-dependent immune responses. This co-stimulatory function is opposed by the negative...Continue reading
CD28-mediated co-stimulation is critical for the regulation of T cell-dependent immune responses. This co-stimulatory function is opposed by the negative...Continue reading
This article describes a novel mechanism for the function of cytotoxic T lymphocyte antigen 4 (CTLA-4) in negative regulation of T cell activation.
CD28-mediated co-stimulation is critical for the regulation of T cell-dependent immune responses. This co-stimulatory function is opposed by the negative regulator CTLA-4. However, the mechanism by which CTLA-4 inhibits T cell responses, whether actively, i.e. through the recruitment of phosphatases, or passively, i.e. through interference with CD28/B7 interactions, has been unclear. This elegant study demonstrates that at least a part of the function of CTLA-4 is due to its ability to grab B7 from antigen-presenting cells and mediate its endocytosis and degradation.
CD28-mediated co-stimulation is critical for the regulation of T cell-dependent immune responses. This co-stimulatory function is opposed by the negative regulator CTLA-4. However, the mechanism by which CTLA-4 inhibits T cell responses, whether actively, i.e. through the recruitment of phosphatases, or passively, i.e. through interference with CD28/B7 interactions, has been unclear. This elegant study demonstrates that at least a part of the function of CTLA-4 is due to its ability to grab B7 from antigen-presenting cells and mediate its endocytosis and degradation.
Disclosures
None declared
Kane L: F1000Prime Recommendation of [Qureshi OS et al., Science 2011, 332(6029):600-3]. In F1000Prime, 01 Jun 2011; DOI: 10.3410/f.10227956.11768055. F1000Prime.com/10227956#eval11768055
06 Jun 2011
New Finding
DOI: 10.3410/f.10227956.11684058
T cell activation requires delivery of multiple signals as a consequence of antigen-specific cells forming cognate interactions with antigen-presenting dendritic cells (DCs). This process initiates when the T cell antigen receptor (TCR) engages peptide/MHC expressed by the DC and proceeds through delivery...Continue reading
T cell activation requires delivery of multiple signals as a consequence of antigen-specific cells forming cognate interactions with antigen-presenting dendritic cells (DCs). This process initiates when the T cell antigen receptor (TCR) engages peptide/MHC expressed by the DC and proceeds through delivery by the DC of a multi-signal process known as costimulation. Costimulation begins when cluster of differentiation 28 (CD28), constitutively expressed by T cells, binds its ligand, CD80/CD86, transiently expressed by activated DCs. As T cells undergo expansion, some of the daughter cells express the cell surface protein cytotoxic T lymphocyte antigen-4 (CTLA-4), which negatively regulates subsequent T cell activation by competing with CD28 for CD80/CD86. The authors show compelling data that CTLA-4 interrupts delivery of costimulation not simply by competition, but rather by an active process termed trans-endocytosis.
The authors use several contrived in vitro model systems to demonstrate that when CTLA-4 binds DC-expressed CD80/CD86, with a 20-fold greater affinity than that seen with CD28, the binding initiates the physical removal of CD80/CD86 from the DC cell surface. The complex is subsequently internalized and directed to lysosomes where the CD80/CD86 molecules are degraded while the CTLA-4 recycles back to the external membrane. This is the process of trans-endocytosis. The fact that lymphocytes are capable of using surface receptors to physically retrieve proteins from the surface of other cells was first shown by Tew and colleagues {1} when they demonstrated that germinal center B cells could use their receptors for antigen (BCRs) to retrieve immune complexes from the surface of follicular dendritic cells. As shown in this paper, trans-endocytosis results in a reduction in surface expression by antigen-presenting cells of key costimulatory molecules required for delivery of costimulation. The authors go on to show that T regulatory (Tregs) cells, known to constitutively express CTLA-4, can also use trans-endocytosis to effectively diminish the costimulatory abilities of antigen-presenting DCs. Importantly, this was shown both in vitro and by looking at real Tregs in situ. Thus, trans-endocytosis represents a new means by which cognate interactions between antigen-reactive T cells and antigen-presenting DCs can be negatively regulated.
The authors use several contrived in vitro model systems to demonstrate that when CTLA-4 binds DC-expressed CD80/CD86, with a 20-fold greater affinity than that seen with CD28, the binding initiates the physical removal of CD80/CD86 from the DC cell surface. The complex is subsequently internalized and directed to lysosomes where the CD80/CD86 molecules are degraded while the CTLA-4 recycles back to the external membrane. This is the process of trans-endocytosis. The fact that lymphocytes are capable of using surface receptors to physically retrieve proteins from the surface of other cells was first shown by Tew and colleagues {1} when they demonstrated that germinal center B cells could use their receptors for antigen (BCRs) to retrieve immune complexes from the surface of follicular dendritic cells. As shown in this paper, trans-endocytosis results in a reduction in surface expression by antigen-presenting cells of key costimulatory molecules required for delivery of costimulation. The authors go on to show that T regulatory (Tregs) cells, known to constitutively express CTLA-4, can also use trans-endocytosis to effectively diminish the costimulatory abilities of antigen-presenting DCs. Importantly, this was shown both in vitro and by looking at real Tregs in situ. Thus, trans-endocytosis represents a new means by which cognate interactions between antigen-reactive T cells and antigen-presenting DCs can be negatively regulated.
References
Disclosures
None declared
Snow E: F1000Prime Recommendation of [Qureshi OS et al., Science 2011, 332(6029):600-3]. In F1000Prime, 06 Jun 2011; DOI: 10.3410/f.10227956.11684058. F1000Prime.com/10227956#eval11684058
29 Jun 2011
Patricia Finn
F1000 Pharmacology & Drug Discovery
University of Illinois at Chicago,
Chicago, IL, USA.
F1000 Pharmacology & Drug Discovery
University of Illinois at Chicago,
Chicago, IL, USA.
Ko-Wei Lin
F1000 Pharmacology & Drug Discovery
University of California, San Diego,
San Diego, CA, USA.
F1000 Pharmacology & Drug Discovery
University of California, San Diego,
San Diego, CA, USA.
New Finding
DOI: 10.3410/f.10227956.12679054
This study suggests a novel function for cytotoxic T lymphocyte antigen 4 (CTLA-4), namely a cell-extrinsic function in immune suppression. CTLA-4 is implicated in removing co-stimulatory ligands (e.g., CD80 and CD86) from antigen-presenting cells via trans-endocytosis, resulting in inhibition of CD28...Continue reading
This study suggests a novel function for cytotoxic T lymphocyte antigen 4 (CTLA-4), namely a cell-extrinsic function in immune suppression. CTLA-4 is implicated in removing co-stimulatory ligands (e.g., CD80 and CD86) from antigen-presenting cells via trans-endocytosis, resulting in inhibition of CD28 co-stimulation of T cells.
CTLA-4 is a negative regulator of T cell immune responses. CTLA-4 expression is increased after T cell activation. CTLA-4 competes with CD28 for binding to CD80 or CD86 via its higher binding affinity to ligands. In this study, CTLA-4-expressing cells deplete CD86 from donor cells and form CD86 vesicles within the CTLA-4+ cells. The trans-endocytosis mechanism results in impaired T cell responses. T cell receptor engagement is shown to enhance CD86 acquisition by CTLA-4+ T cells or CTLA-4 T regulatory cells. Using both in vitro human and mouse models and in vivo mouse models, this study suggests that the trans-endocytosis mechanism is dependent upon CTLA-4 and also works in an antigen-dependent manner.
The mechanism by which CTLA-4 functions is evolving. A future study of proteomic and transcriptomic mechanisms may answer questions regarding CTLA-4 signaling pathways in regulating T cells. Why would cells use energy to transfer CD80 or CD86 to T cells? Will CD80 or CD86 induce signals or provide information to T cells?
CTLA-4 is a negative regulator of T cell immune responses. CTLA-4 expression is increased after T cell activation. CTLA-4 competes with CD28 for binding to CD80 or CD86 via its higher binding affinity to ligands. In this study, CTLA-4-expressing cells deplete CD86 from donor cells and form CD86 vesicles within the CTLA-4+ cells. The trans-endocytosis mechanism results in impaired T cell responses. T cell receptor engagement is shown to enhance CD86 acquisition by CTLA-4+ T cells or CTLA-4 T regulatory cells. Using both in vitro human and mouse models and in vivo mouse models, this study suggests that the trans-endocytosis mechanism is dependent upon CTLA-4 and also works in an antigen-dependent manner.
The mechanism by which CTLA-4 functions is evolving. A future study of proteomic and transcriptomic mechanisms may answer questions regarding CTLA-4 signaling pathways in regulating T cells. Why would cells use energy to transfer CD80 or CD86 to T cells? Will CD80 or CD86 induce signals or provide information to T cells?
Disclosures
None declared
Finn P and Lin K: F1000Prime Recommendation of [Qureshi OS et al., Science 2011, 332(6029):600-3]. In F1000Prime, 29 Jun 2011; DOI: 10.3410/f.10227956.12679054. F1000Prime.com/10227956#eval12679054
14 Jul 2011
New Finding
DOI: 10.3410/f.10227956.12934054
This study provides compelling evidence for a cell-extrinsic mechanism of action for cytotoxic T lymphocyte antigen 4 (CTLA-4) that can explain many of the effects of CTLA-4 in suppressing immune responses. However, it is not clear that this endocytic mechanism explains all of CTLA-4's effects.
CTL4...Continue reading
CTL4...Continue reading
This study provides compelling evidence for a cell-extrinsic mechanism of action for cytotoxic T lymphocyte antigen 4 (CTLA-4) that can explain many of the effects of CTLA-4 in suppressing immune responses. However, it is not clear that this endocytic mechanism explains all of CTLA-4's effects.
CTLA-4 is a critical negative regulator in the immune system. CTLA-4-deficient mice die early in life from a lymphoproliferative disorder that leads to multi-organ inflammation {1,2}. Evidence has accumulated that CTLA-4 can influence T cell responses through effects on regulatory T cells (Tregs), as well as through effects on the responding effector T cells (Teffs) (see, for example, {3,4} and references therein). This study by Qureshi et al. now provides a unifying model that is consistent with CTLA-4 - on both effector and regulatory cells - inducing a similar cell-extrinsic effect to limit T cell activation. They show that CTLA-4-expressing cells deplete CD80 and CD86 from antigen-presenting cells by an endocytic process. Deletion of the conserved cytoplasmic tail of CTLA-4, which is required for endocytosis, as well as blockade of CTLA-4 but not CD28, impair this process. The data provide a compelling explanation for how CTLA-4 on either Tregs or Teffs inhibits T cell activation, by depriving CD28 of its ligands. As pointed out by the authors, this mechanism provides a rationale for having CTLA-4 and CD28 binding to the same ligands and a logical explanation for why CTLA accumulates in endosomes. The removal of CD28's ligands by CTLA-4 either on the responding T cells or on the Tregs can account for many observations of how CTLA-4 limits immune responses, such as by decreased signaling through the T cell receptor, impaired synapse formation and increased T cell mobility {5}. Moreover, the requirement for the CTLA-4 cytoplasmic tail for this endocytic function might explain some of the previous mutagenesis studies on the role of the CTLA-4 cytoplasmic tail {5}. The question now arises as to whether this mechanism can account for all the effects of CTLA-4. Mice in which CTLA-4 is deleted only on Foxp3-positive Tregs still die of multi-organ inflammation, albeit with a substantial delay compared to mice completely lacking CTLA-4 {4}. This argues that CTLA-4 on Teff cells contributes to, but is not sufficient for control of, T cell responses. If CTLA-4 on either Tregs or Teff cells can endocytose and remove CD80/86, why then is CTLA-4 on effector cells alone not sufficient? Is it simply a quantitative defect in the overall amount of CTLA-4 or are we missing additional mechanisms of CTLA-4 action on Tregs? The endocytosis model also fails to explain some of the earlier in vitro data that showed that CTLA-4 cross-linking impairs activation of CD3/CD28-activated T cells {6}, thus, there may still be additional T cell-intrinsic effects of CTLA-4 that require further investigation.
CTLA-4 is a critical negative regulator in the immune system. CTLA-4-deficient mice die early in life from a lymphoproliferative disorder that leads to multi-organ inflammation {1,2}. Evidence has accumulated that CTLA-4 can influence T cell responses through effects on regulatory T cells (Tregs), as well as through effects on the responding effector T cells (Teffs) (see, for example, {3,4} and references therein). This study by Qureshi et al. now provides a unifying model that is consistent with CTLA-4 - on both effector and regulatory cells - inducing a similar cell-extrinsic effect to limit T cell activation. They show that CTLA-4-expressing cells deplete CD80 and CD86 from antigen-presenting cells by an endocytic process. Deletion of the conserved cytoplasmic tail of CTLA-4, which is required for endocytosis, as well as blockade of CTLA-4 but not CD28, impair this process. The data provide a compelling explanation for how CTLA-4 on either Tregs or Teffs inhibits T cell activation, by depriving CD28 of its ligands. As pointed out by the authors, this mechanism provides a rationale for having CTLA-4 and CD28 binding to the same ligands and a logical explanation for why CTLA accumulates in endosomes. The removal of CD28's ligands by CTLA-4 either on the responding T cells or on the Tregs can account for many observations of how CTLA-4 limits immune responses, such as by decreased signaling through the T cell receptor, impaired synapse formation and increased T cell mobility {5}. Moreover, the requirement for the CTLA-4 cytoplasmic tail for this endocytic function might explain some of the previous mutagenesis studies on the role of the CTLA-4 cytoplasmic tail {5}. The question now arises as to whether this mechanism can account for all the effects of CTLA-4. Mice in which CTLA-4 is deleted only on Foxp3-positive Tregs still die of multi-organ inflammation, albeit with a substantial delay compared to mice completely lacking CTLA-4 {4}. This argues that CTLA-4 on Teff cells contributes to, but is not sufficient for control of, T cell responses. If CTLA-4 on either Tregs or Teff cells can endocytose and remove CD80/86, why then is CTLA-4 on effector cells alone not sufficient? Is it simply a quantitative defect in the overall amount of CTLA-4 or are we missing additional mechanisms of CTLA-4 action on Tregs? The endocytosis model also fails to explain some of the earlier in vitro data that showed that CTLA-4 cross-linking impairs activation of CD3/CD28-activated T cells {6}, thus, there may still be additional T cell-intrinsic effects of CTLA-4 that require further investigation.
References
1.
Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4.
Immunity 1995 Nov; 5(3):541-7
PMID: 7584144
2.
Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4.
Science 1995 Nov 10; 5238(270):985-8
PMID: 7481803
3.
CTLA-4 suppresses the pathogenicity of self antigen-specific T cells by cell-intrinsic and cell-extrinsic mechanisms.
Nat Immunol 2010 Feb; 2(11):129-35
PMID: 20037585
4.
CTLA-4 control over Foxp3+ regulatory T cell function.
Science 2008 Oct 10; 5899(322):271-5
PMID: 18845758
5.
CD28 and CTLA-4 coreceptor expression and signal transduction.
Immunol Rev 2009 May; 1(229):12-26
PMID: 19426212
6.
CTLA-4 can function as a negative regulator of T cell activation.
Immunity 1994 Aug; 5(1):405-13
PMID: 7882171
Disclosures
None declared
Watts T: F1000Prime Recommendation of [Qureshi OS et al., Science 2011, 332(6029):600-3]. In F1000Prime, 14 Jul 2011; DOI: 10.3410/f.10227956.12934054. F1000Prime.com/10227956#eval12934054
F1000Prime Recommendations, Dissents and Comments for [Qureshi OS et al., Science 2011, 332(6029):600-3]. In F1000Prime, 25 May 2013; F1000Prime.com/10227956
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Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an essential negative regulator of T cell immune responses whose mechanism of action is the subject of debate. CTLA-4 shares two ligands (CD80 and CD86) with a stimulatory receptor, CD28. Here, we show that CTLA-4 can capture its ligands from opposing cells by a process of trans-endocytosis. After removal, these costimulatory ligands are degraded inside CTLA-4-expressing cells, resulting in impaired costimulation via CD28. Acquisition of CD86 from antigen-presenting cells is stimulated by T cell receptor engagement and observed in vitro and in vivo. These data reveal a mechanism of immune regulation in which CTLA-4 acts as an effector molecule to inhibit CD28 costimulation by the cell-extrinsic depletion of ligands, accounting for many of the known features of the CD28-CTLA-4 system.
PMID: 21474713
