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T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse.
J Exp Med. 2011 Jun 6; 208(6):1279-89
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27 May 2011
Confirmation, New Finding, Technical Advance
DOI: 10.3410/f.10816957.11727055
This article reports the exciting development of a T cell receptor (TCR) signal strength reporter mouse. By expressing green fluorescent protein (GFP) from the Nr4a1 (Nur77) locus, Moran et al. have developed a mouse which reliably reports strength of TCR signal through intensity of GFP expression.
Unlike...Continue reading
Unlike...Continue reading
This article reports the exciting development of a T cell receptor (TCR) signal strength reporter mouse. By expressing green fluorescent protein (GFP) from the Nr4a1 (Nur77) locus, Moran et al. have developed a mouse which reliably reports strength of TCR signal through intensity of GFP expression.
Unlike CD69 expression (i.e. upregulation following TCR activation or inflammatory signals such as interferon-alpha {1,2}), GFP expression in their Nur77GFP mouse is only upregulated following TCR stimulation but not in the face of in vitro inflammatory cues or in vivo infection.
Using this mouse, the authors confirm the previously proposed notion that regulatory T cells (Treg) compete for rare high-affinity TCR ligands in the thymus {3,4}. This report also evaluates aspects of TCR signal strength in Treg and invariant natural-killer T cell development using this new tool. The Nur77GFP TCR signal strength reporter mouse will undoubtedly be an invaluable tool in further studies of TCR signal strength in lymphocyte development, homeostasis, and immunity.
Unlike CD69 expression (i.e. upregulation following TCR activation or inflammatory signals such as interferon-alpha {1,2}), GFP expression in their Nur77GFP mouse is only upregulated following TCR stimulation but not in the face of in vitro inflammatory cues or in vivo infection.
Using this mouse, the authors confirm the previously proposed notion that regulatory T cells (Treg) compete for rare high-affinity TCR ligands in the thymus {3,4}. This report also evaluates aspects of TCR signal strength in Treg and invariant natural-killer T cell development using this new tool. The Nur77GFP TCR signal strength reporter mouse will undoubtedly be an invaluable tool in further studies of TCR signal strength in lymphocyte development, homeostasis, and immunity.
References
1.
The CD69 receptor: a multipurpose cell-surface trigger for hematopoietic cells.
Immunol Today 1994 Oct; 10(15):479-83
PMID: 7945773
2.
CD69 acts downstream of interferon-alpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs.
Nature 2006 Mar 23; 7083(440):540-4
PMID: 16525420
3.
Intraclonal competition limits the fate determination of regulatory T cells in the thymus.
Nat Immunol 2009 Jun; 6(10):610-7
PMID: 19430476
4.
TCR-dependent differentiation of thymic Foxp3+ cells is limited to small clonal sizes.
J Exp Med 2009 Sep 28; 10(206):2121-30
PMID: 19737865
Disclosures
None declared
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Turka L and Lieberman S: F1000Prime Recommendation of [Moran AE et al., J Exp Med 2011, 208(6):1279-89]. In F1000Prime, 27 May 2011; DOI: 10.3410/f.10816957.11727055. F1000Prime.com/10816957#eval11727055
31 May 2011
New Finding, Technical Advance
DOI: 10.3410/f.10816957.11760057
This study provides an exciting new tool that can provide a quantitative read-out of T cell receptor (TCR) signaling in T cell and thymocyte populations in situ. The study also provides important new information about the role of TCR signaling in the development of regulatory T cells (Tregs) and invariant...Continue reading
This study provides an exciting new tool that can provide a quantitative read-out of T cell receptor (TCR) signaling in T cell and thymocyte populations in situ. The study also provides important new information about the role of TCR signaling in the development of regulatory T cells (Tregs) and invariant natural killer (iNK) T cells.
This manuscript describes a novel in vivo fluorescent reporter to read-out TCR signal strength. The authors document the fidelity and utility of the reporter in a variety of settings, and then go on to use the reporter to address a number of important and unresolved issues regarding T cell development. Of particular interest is the evidence that the limiting factor for thymic development of Tregs is the availability of TCR ligands. Also of interest is evidence that iNKT cells receive strong signals during their development in the thymus, but not after they migrate to the periphery.
This manuscript describes a novel in vivo fluorescent reporter to read-out TCR signal strength. The authors document the fidelity and utility of the reporter in a variety of settings, and then go on to use the reporter to address a number of important and unresolved issues regarding T cell development. Of particular interest is the evidence that the limiting factor for thymic development of Tregs is the availability of TCR ligands. Also of interest is evidence that iNKT cells receive strong signals during their development in the thymus, but not after they migrate to the periphery.
Disclosures
None declared
Robey E: F1000Prime Recommendation of [Moran AE et al., J Exp Med 2011, 208(6):1279-89]. In F1000Prime, 31 May 2011; DOI: 10.3410/f.10816957.11760057. F1000Prime.com/10816957#eval11760057
13 Jun 2011
New Finding
DOI: 10.3410/f.10816957.12093054
This paper describes a novel strain of mice that express green fluorescent protein (GFP) under the control of the Nur77 regulator elements. Amazingly, GFP expression in T cells of these mice correlates nicely with the strength of the T cell receptor (TCR) stimulation.
Nur77 was initially isolated...Continue reading
Nur77 was initially isolated...Continue reading
This paper describes a novel strain of mice that express green fluorescent protein (GFP) under the control of the Nur77 regulator elements. Amazingly, GFP expression in T cells of these mice correlates nicely with the strength of the T cell receptor (TCR) stimulation.
Nur77 was initially isolated as an immediate early gene that can be induced by many stimuli. In T cell lines/hybridomas, stimulation that leads to apoptosis elicits a strong and prolonged expression of Nur77, while proliferating signals induce only transient expression {1}. This paper shows that the strength of Nur77 in vivo expression (through GFP) directly correlates with the strength of TCR signals during T cell development.
In these Nur77-GFP mice, GFP signals can be detected in positively selecting cells, but negatively selecting immature T cells express yet a higher level of GFP expression. Indeed, GFP expression in Nur77-GFP/OT-1 TCR transgenic mice correlates linearly with the potency of the presented OVA peptides in a co-culture experiment. This strain of mice thus presents a novel in vivo tool that can be used to understand how the strength of TCR signals shape T cell repertoire, including those of regulatory T cells (Treg) and natural killer (NK)T cells.
Nur77 was initially isolated as an immediate early gene that can be induced by many stimuli. In T cell lines/hybridomas, stimulation that leads to apoptosis elicits a strong and prolonged expression of Nur77, while proliferating signals induce only transient expression {1}. This paper shows that the strength of Nur77 in vivo expression (through GFP) directly correlates with the strength of TCR signals during T cell development.
In these Nur77-GFP mice, GFP signals can be detected in positively selecting cells, but negatively selecting immature T cells express yet a higher level of GFP expression. Indeed, GFP expression in Nur77-GFP/OT-1 TCR transgenic mice correlates linearly with the potency of the presented OVA peptides in a co-culture experiment. This strain of mice thus presents a novel in vivo tool that can be used to understand how the strength of TCR signals shape T cell repertoire, including those of regulatory T cells (Treg) and natural killer (NK)T cells.
References
1.
Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas.
Nature 1994 Jan 20; 6460(367):277-81
PMID: 8121493
Disclosures
None declared
Winoto A: F1000Prime Recommendation of [Moran AE et al., J Exp Med 2011, 208(6):1279-89]. In F1000Prime, 13 Jun 2011; DOI: 10.3410/f.10816957.12093054. F1000Prime.com/10816957#eval12093054
17 Jun 2011
New Finding, Technical Advance
DOI: 10.3410/f.10816957.12312056
Up to the present time, it has been impossible to differentiate T cell activation by T cell receptor (TCR)-dependent versus TCR-independent means, e.g. the inflammation-dependent fashion in vivo. In this study, the authors were able to monitor, for the first time, the level of TCR-mediated activation...Continue reading
Up to the present time, it has been impossible to differentiate T cell activation by T cell receptor (TCR)-dependent versus TCR-independent means, e.g. the inflammation-dependent fashion in vivo. In this study, the authors were able to monitor, for the first time, the level of TCR-mediated activation in vivo, by generating and using transgenic mice expressing green fluorescent protein (GFP) from the immediate early gene Nr4a1 (Nur77) locus.
The transgenic mice were generated by inserting GFP into the Nr4a1 (Nur77) locus of a bacterial artificial chromosome (BAC). As a result, not only was GFP up-regulated with T cells by TCR ligation in these mice, but the differential expression of GFP by T cells can also be observed based on the strength of TCR signaling. Using these transgenic mice, the authors were able to show that regulatory T cells (Treg cells) and invariant natural killer T (NKT) cells (iNKT cells) perceived stronger TCR signals than conventional T cells during development. Furthermore, it was shown that while Treg cells continued to perceive strong TCR stimuli, compared to conventional T cells upon selection in the thymus, iNKT cells only discerned the stronger TCR signals transiently. Finally, cluster of differentiation 69 (CD69) expression, which has been used as an indicator of T cell activation, is up-regulated not only by TCR-mediated activation but also by inflammatory stimuli {1,2}, thus limiting its use as a marker of TCR stimulation. In this regard, these transgenic mice are able to differentiate CD69 up-regulation triggered by the TCR-dependent pathway from that by the TCR-independent, inflammation-dependent fashion. Overall, these mice will be a useful tool for tracking and monitoring activated T cells in vivo under various experimental settings that include acute and chronic infection, cancer, and transplantation.
The transgenic mice were generated by inserting GFP into the Nr4a1 (Nur77) locus of a bacterial artificial chromosome (BAC). As a result, not only was GFP up-regulated with T cells by TCR ligation in these mice, but the differential expression of GFP by T cells can also be observed based on the strength of TCR signaling. Using these transgenic mice, the authors were able to show that regulatory T cells (Treg cells) and invariant natural killer T (NKT) cells (iNKT cells) perceived stronger TCR signals than conventional T cells during development. Furthermore, it was shown that while Treg cells continued to perceive strong TCR stimuli, compared to conventional T cells upon selection in the thymus, iNKT cells only discerned the stronger TCR signals transiently. Finally, cluster of differentiation 69 (CD69) expression, which has been used as an indicator of T cell activation, is up-regulated not only by TCR-mediated activation but also by inflammatory stimuli {1,2}, thus limiting its use as a marker of TCR stimulation. In this regard, these transgenic mice are able to differentiate CD69 up-regulation triggered by the TCR-dependent pathway from that by the TCR-independent, inflammation-dependent fashion. Overall, these mice will be a useful tool for tracking and monitoring activated T cells in vivo under various experimental settings that include acute and chronic infection, cancer, and transplantation.
References
Disclosures
None declared
Tsuji M: F1000Prime Recommendation of [Moran AE et al., J Exp Med 2011, 208(6):1279-89]. In F1000Prime, 17 Jun 2011; DOI: 10.3410/f.10816957.12312056. F1000Prime.com/10816957#eval12312056
F1000Prime Recommendations, Dissents and Comments for [Moran AE et al., J Exp Med 2011, 208(6):1279-89]. In F1000Prime, 20 May 2013; F1000Prime.com/10816957
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The ability of antigen receptors to engage self-ligands with varying affinity is crucial for lymphocyte development. To further explore this concept, we generated transgenic mice expressing GFP from the immediate early gene Nr4a1 (Nur77) locus. GFP was up-regulated in lymphocytes by antigen receptor stimulation but not by inflammatory stimuli. In T cells, GFP was induced during positive selection, required major histocompatibility complex for maintenance, and directly correlated with the strength of T cell receptor (TCR) stimulus. Thus, our results define a novel tool for studying antigen receptor activation in vivo. Using this model, we show that regulatory T cells (T(reg) cells) and invariant NKT cells (iNKT cells) perceived stronger TCR signals than conventional T cells during development. However, although T(reg) cells continued to perceive strong TCR signals in the periphery, iNKT cells did not. Finally, we show that T(reg) cell progenitors compete for recognition of rare stimulatory TCR self-ligands.
DOI: 10.1084/jem.20110308
PMID: 21606508
