Breakdown in Repression of IFN-γ mRNA Leads to Accumulation of Self-Reactive Effector CD8+ T Cells

Chang, Pheh-Ping; Lee, Sau K.; Hu, Xin; Davey, Gayle M.; Duan, Guowen; Cho, Jae-Ho; Karupiah, Gunasegaran; Sprent, Jonathan; Heath, William R.; Bertram, Edward M.; Vinuesa, Carola G.

doi:10.4049/jimmunol.1102432

Cited by 21 publications

(22 citation statements)

References 44 publications

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“…This is consistent with the finding of a population of SLECs in the spleen of Rc3h1 −/− mice [6]. Similar findings linked to increased IFN-γ synthesis have been described for Roquin san/san mice [26]. Additional studies are planned in our laboratory using adoptive transfer experiments to trace the homing properties of the Roquin san/san SLECs to the gut, and using IL-7R expression to differentiate MLN SLECs from memory precursor effector cells (MPECs) [27].…”

Section: Discussionsupporting

confidence: 85%

Small Intestine Inflammation in Roquin-Mutant and Roquin-Deficient Mice

et al. 2013

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Roquin, an E3 ubiquitin ligase that localizes to cytosolic RNA granules, is involved in regulating mRNA stability and translation. Mice that have a M199R mutation in the Roquin protein (referred to as sanroque or Roquinsan/san mice) develop autoimmune pathologies, although the extent to which these occur in the intestinal mucosa has not been determined. Here, we demonstrate that Roquinsan/san mice reproducibly develop intestinal inflammation in the small intestine but not the colon. Similarly, mice generated in our laboratory in which the Roquin gene was disrupted by insertion of a gene trap cassette (Roquingt/gt mice) had small intestinal inflammation that mimicked that of Roquinsan/san mice. MLN cells in Roquinsan/san mice consisted of activated proliferating T cells, and had increased numbers of CD44hi CD62Llo KLRG1+ short-lived effector cells. Proportionally more small intestinal intraepithelial lymphocytes in Roquinsan/san mice expressed the ICOS T cell activation marker. Of particular interest, small intestinal lamina propria lymphocytes in Roquinsan/san mice consisted of a high proportion of Gr-1+ T cells that included IL-17A+ cells and CD8+ IFN-γ+ cells. Extensive cytokine dysregulation resulting in both over-expression and under-expression of chemotactic cytokines occurred in the ileum of Roquinsan/san mice, the region most prone to the development of inflammation. These findings demonstrate that chronic inflammation ensues in the intestine following Roquin alteration either as a consequence of protein mutation or gene disruption, and they have implications for understanding how small intestinal inflammation is perpetuated in Crohn's disease (CD). Due to the paucity of animal models of CD-like pathophysiology in the small intestine, and because the primary gene/protein defects of the Roquin animal systems used here are well-defined, it will be possible to further elucidate the underlying genetic and molecular mechanisms that drive the disease process.

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Section: Discussionsupporting

confidence: 85%

Small Intestine Inflammation in Roquin-Mutant and Roquin-Deficient Mice

et al. 2013

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“…Both IL-2 21,39–41 and IFN-γ 42,43 have been shown to individually program GzmB expression in T cells, and our current data extend these findings by demonstrating that these two cytokines can cooperate to program maximal GzmB expression. Somewhat paradoxically, however, IFN-γ controls the responsiveness of these effector T cells to IL-2 by limiting the expression of the IL-2 receptor alpha chain (CD25) that confers high affinity binding.…”

Section: Discussionsupporting

confidence: 83%

“…Both IL-2 21,39–41 and IFN-γ 42,43 can program T cells to express GzmB. Our current data indicate that the two cytokines cooperate in dual-costimulated T cells to program maximal GzmB expression (Figure 1b).…”

Section: Resultsmentioning

confidence: 52%

CD134/CD137 dual costimulation‐elicited IFN‐γ maximizes effector T‐cell function but limits Treg expansion

et al. 2013

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T cell tolerance to tumor antigens represents a major hurdle in generating tumor immunity. Combined administration of agonistic monoclonal antibodies to the costimulatory receptors CD134 plus CD137 can program T cells responding to tolerogenic antigen to undergo expansion and effector T cell differentiation, and also elicits tumor immunity. Nevertheless, CD134 and CD137 agonists can also engage inhibitory immune components. To understand how immune stimulatory versus inhibitory components are regulated during CD134 plus CD137 dual costimulation, the current study utilized a model where dual costimulation programs T cells encountering a highly tolerogenic self-antigen to undergo effector differentiation. IFN-γ was found to play a pivotal role in maximizing the function of effector T cells while simultaneously limiting the expansion of CD4+CD25+Foxp3+ Tregs. In antigen-responding effector T cells, IFN-γ operates via a direct cell-intrinsic mechanism to cooperate with IL-2 to program maximal expression of granzyme B. Simultaneously, IFN-γ limits expression of the IL-2 receptor alpha chain (CD25) and IL-2 signaling through a mechanism that does not involve T-bet-mediated repression of IL-2. IFN-γ also limited CD25 and Foxp3 expression on bystanding CD4+Foxp3+ Tregs, and limited the potential of these Tregs to expand. These effects could not be explained by the ability of IFN-γ to limit IL-2 availability. Taken together, during dual costimulation IFN-γ interacts with IL-2 through distinct mechanisms to program maximal expression of effector molecules in antigen-responding T cells while simultaneously limiting Treg expansion.

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“…So, decreased KLRG1 + cell numbers could reflect the actions of the Tregs to reduce the IL-12 driven autoimmune process which is critical to the dnTGFβRII model [34,35]. Excess IFNγ can also drive the expression of frankly autoreactive KLRG1 + CD8 T cells, as shown by the increased numbers of these cells in mice expressing the sanroquin mutation of Roquin [36]. Finally, recent studies in tumor immunology have shown that KLRG1 + CD8 cells are cytotoxic to tumor tissue [37—39], supporting the hypothesis that KLRG1 + CD8 cells may mediate hepatic autoimmunity by causing cholangiocyte cell death.…”

Section: Discussionmentioning

confidence: 99%

Murine autoimmune cholangitis requires two hits: Cytotoxic KLRG1+ CD8 effector cells and defective T regulatory cells

Huang¹,

Kachapati²,

Adams³

et al. 2014

Journal of Autoimmunity

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Primary biliary cirrhosis (PBC) is an enigmatic disease mediated by autoimmune destruction of cholangiocytes in hepatic bile ducts. The early immunological events leading to PBC are poorly understood; clinical signs of disease occur very late in the pathological process. We have used our unique murine model of PBC in dominant-negative TGF-β receptor type II transgenic mice to delineate critical early immunopathological pathways, and previously showed that dnTGFbRII CD8 T cells transfer biliary disease. Herein we report significantly increased numbers of hepatic dnTGFβRII terminally differentiated (KLRG1+) CD8 T cells, a CD8 subset previously shown to be enriched in antigen specific cells during hepatic immune response to viral infections. We performed bone marrow chimera studies to assess whether dnTGFbRII CD8 mediated disease was cell intrinsic or extrinsic. Unexpectedly, mixed (dnTGFβRII and B6) bone marrow chimeric (BMC) mice were protected from biliary disease compared to dnTGFβRII single bone marrow chimerics. To define the protective B6 cell subset, we performed adoptive transfer studies, which showed that co-transfer of B6 Tregs prevented dnTGFbRII CD8 T cell mediated cholangitis. Treg mediated disease protection was associated with significantly decreased numbers of hepatic KLRG1+ CD8 T cells. In contrast, co-transfer of dnTGFβRII Tregs offered no protection, and dnTGFβRII Treg cells were functionally defective in suppressing effector CD8 T cells in vitro compared to wild type B6 Tregs. In vitro cholangiocyte cytotoxicity assays demonstrated significantly increased numbers of cytotoxic hepatic dnTGFβRII KLRG1+ CD8 cells compared to B6. Protection from disease by B6 Tregs was associated with elimination of hepatic dnTGFβRII CD8 mediated cholangiocyte cytotoxicity. These results emphasize that autoimmune cholangitis requires defects in both the T effector and regulatory compartments, and that an intrinsic T cell effector defect is not sufficient to mediate autoimmune biliary disease in the setting of intact immune regulation. These results have important implications for understanding the early pathogenesis of human PBC.

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Breakdown in Repression of IFN-γ mRNA Leads to Accumulation of Self-Reactive Effector CD8+ T Cells

Cited by 21 publications

References 44 publications

Small Intestine Inflammation in Roquin-Mutant and Roquin-Deficient Mice

Small Intestine Inflammation in Roquin-Mutant and Roquin-Deficient Mice

CD134/CD137 dual costimulation‐elicited IFN‐γ maximizes effector T‐cell function but limits Treg expansion

Murine autoimmune cholangitis requires two hits: Cytotoxic KLRG1+ CD8 effector cells and defective T regulatory cells

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