Preferential Development of CD4 and CD8 T Regulatory Cells in RasGRP1-Deficient Mice

Chen, Xiaoxi; Priatel, John J.; Chow, Michael; Teh, Hung‐Sia

doi:10.4049/jimmunol.180.9.5973

Cited by 42 publications

(40 citation statements)

References 45 publications

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“…The findings that thymocyte positive selection is relatively inefficient in the absence of RasGRP1 demonstrate that these Ras GEFs are not functionally redundant (6,9,10). Moreover, aberrant positive selection in RasGRP1-deficient mice is associated with an abundance of activated-and memory-phenotype peripheral CD4 and CD8 T cells (9,18,39), a likely result of chronic immunodeficiency (18) and/or a breakdown in T cell tolerance (9). Therefore, studies of mature T cells in non-TCR Tg RasGRP1 2/2 mice are tenuous because their differentiation status, a factor that influences TCR signal transduction (40), does not match wild-type.…”

Section: Discussionmentioning

confidence: 89%

RasGRP1 Regulates Antigen-Induced Developmental Programming by Naive CD8 T Cells

Priatel

Chen

Huang

et al. 2009

The Journal of Immunology

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Ag encounter by naive CD8 T cells initiates a developmental program consisting of cellular proliferation, changes in gene expression, and the formation of effector and memory T cells. The strength and duration of TCR signaling are known to be important parameters regulating the differentiation of naive CD8 T cells, although the molecular signals arbitrating these processes remain poorly defined. The Ras-guanyl nucleotide exchange factor RasGRP1 has been shown to transduce TCR-mediated signals critically required for the maturation of developing thymocytes. To elucidate the role of RasGRP1 in CD8 T cell differentiation, in vitro and in vivo experiments were performed with 2C TCR transgenic CD8 T cells lacking RasGRP1. In this study, we report that RasGRP1 regulates the threshold of T cell activation and Ag-induced expansion, at least in part, through the regulation of IL-2 production. Moreover, RasGRP1−/− 2C CD8 T cells exhibit an anergic phenotype in response to cognate Ag stimulation that is partially reversible upon the addition of exogenous IL-2. By contrast, the capacity of IL-2/IL-2R interactions to mediate Ras activation and CD8 T cell expansion and differentiation appears to be largely RasGRP1-independent. Collectively, our results demonstrate that RasGRP1 plays a selective role in T cell signaling, controlling the initiation and duration of CD8 T cell immune responses.

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Section: Discussionmentioning

confidence: 89%

RasGRP1 Regulates Antigen-Induced Developmental Programming by Naive CD8 T Cells

Priatel

Chen

Huang

et al. 2009

The Journal of Immunology

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“…Early evidence demonstrated that RasGRP1 is important for T cell development (4,6,17), but that it had little impact on B cell development (2). Despite this, Rasgrp1 2/2 mice displayed high levels of serum autoantibodies (2), suggesting that it may be necessary to examine self-reactive B cells directly to understand whether RasGRP1 contributes to B cell development.…”

Section: Discussionmentioning

confidence: 99%

Multiple Checkpoint Breach of B Cell Tolerance in Rasgrp1-Deficient Mice

Bartlett

Buhlmann

Stone

et al. 2013

The Journal of Immunology

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Lymphopenic hosts offer propitious microenvironments for expansion of autoreactive B and T cells. Despite this, many lymphopenic hosts do not develop autoimmune disease, suggesting that additional factors are required for breaching self-tolerance in the setting of lymphopenia. Mice deficient in guanine nucleotide exchange factor Rasgrp1 develop a lymphoproliferative disorder with features of human systemic lupus erythematosus. Early in life, Rasgrp1-deficient mice have normal B cell numbers but are T lymphopenic, leading to defective homeostatic expansion of CD4 T cells. To investigate whether B cell–intrinsic mechanisms also contribute to autoimmunity, Rasgrp1-deficient mice were bred to mice containing a knockin autoreactive BCR transgene (564Igi), thereby allowing the fate of autoreactive B cells to be assessed. During B cell development, the frequency of receptor-edited 564Igi B cells was reduced in Rasrp1-deficient mice compared with Rasgrp1-sufficient littermate control mice, suggesting that tolerance was impaired. In addition, the number of 564Igi transitional B cells was increased in Rasgrp1-deficient mice compared with control mice. Immature 564Igi B cells in bone marrow and spleen lacking RasGRP1 expressed lower levels of Bim mRNA and protein, suggesting that autoreactive B cells elude clonal deletion during development. Concomitant with increased serum autoantibodies, Rasgrp1-deficient mice developed spontaneous germinal centers at 8–10 wk of age. The frequency and number of 564Igi B cells within these germinal centers were significantly increased in Rasgrp1-deficient mice relative to control mice. Taken together, these studies suggest that autoreactive B cells lacking Rasgrp1 break central and peripheral tolerance through both T cell–independent and –dependent mechanisms.

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“…However, if the evidence proving CD8 ϩ CD122 ϩ cells are regulatory T cells is weak, the evidence to prove CD8 ϩ CD122 ϩ cells are memory T cells is also weak or at least not significantly stronger. In fact, Chen et al demonstrated the regulatory activity of CD8 ϩ CD122 ϩ cells with original methods, further supporting the validity of CD8 ϩ CD122 ϩ cells as regulatory T cells [43].…”

Section: Cd8 ؉ Cd122 ؉ Cells Are Regulatory T Cellsmentioning

confidence: 92%