Gld mutation of Fas ligand increases the frequency and up-regulates cell survival genes in CD25+CD4+ TR cells

Abstract

The Fas pathway and regulatory T (T(R)) cells play intertwining roles in controlling T cell tolerance through deletion and suppression of autoreactive T cells. Impairment of either mechanism causes severe T cell lymphoproliferation albeit with opposing outcomes. T cell lymphoproliferation induced by defective Fas pathway does not cause overt lymphocytic infiltration but rather prevents an important set of T cell-mediated autoimmune diseases. In contrast, deficiency in T(R) cell causes fulminant autoimmunity in very early life and fatal lymphocytic infiltration. These observations suggest existence of unidirectional fail/safe mechanism that compensate for defects in the Fas pathway but not in regulatory cells. To gain insights into how animals compensate for defects in the Fas system, we analyzed the impact of generalized lymphoproliferative disease (gld) mutation on survival, function and transcription profile of CD25+CD4+ T(R) cells. Our results show that all CD4 T cells expanded in gld mice. However, CD25+CD4+ T(R) cells are disproportionately increased in the pool of CD4 T cells perhaps due to their unique apoptosis phenotype. Freshly isolated CD25+CD4+ T(R) cells, unlike CD25-CD4+ T cells, are highly sensitive to FasL-induced apoptosis in the steady state. CD25+CD4+ T(R) cells that accumulate in gld mice express similar level of Foxp3, and have suppression potency and T(R) gene expression profile as wild-type CD25+CD4+ T(R) cells. Furthermore, the transcription profile of gld CD25+CD4+ T(R) cells is characterized by differential expression of genes involved in cell survival, metabolism and innate immune responses. These results provide a strong cellular and molecular basis for understanding why impaired Fas pathway prevents an important subset of T cell-mediated autoimmune diseases.

Autoantibody production in lpr/lpr gld/gld mice reflects accumulation of CD4+ effector cells that are resistant to regulatory T cell activity

“…We found that Treg cells derived from both young and old lpr/lpr gld/gld mice ably suppress T cell proliferation in vitro. These data are consistent with other studies that have shown that blocking with an anti-FasL antibody has no effect on Treg cell suppression [39,40], and that Treg cells from gld/gld mice can inhibit gld/gld Th cell proliferation [11]. Conversely, we found that Treg cells suppress the proliferation of Th cells derived from either young or old lpr/lpr gld/gld mice.…”

“…Likewise, in some murine models of SLE Treg cells are diminished and/or have reduced Foxp3 protein expression [8][9][10]. In contrast, 16-20 week old C3H gld/gld mice have an increased frequency of Foxp3 + T cells with Foxp3 protein expressed at levels similar to normal mice [11]. The functional capacity of Treg cells to block T cell proliferation in vitro also varies according to strain.…”

“…The functional capacity of Treg cells to block T cell proliferation in vitro also varies according to strain. In the C3H gld/gld model, Treg cells inhibited Th cell proliferation while in NZM2410 mice the Treg cells were less effective [10,11]. The ability of Treg cells to block lupus in vivo has also depended upon the symptoms examined.…”

Double-Negative αβ T Cells Are Early Responders to AKI and Are Found in Human Kidney

“…Forty nanograms of cDNA of each sample was used for each real-time PCR reaction using gene-specific primer and probe sets in the Quant Studio 12 K Flex real-time PCR system. Realtime data were normalized with b-actin and analyzed as previously described 31 and fold change in mRNA expression was calculated using the 2-ΔΔCT method.…”

Foxp3-Mediated Suppression of CD95L Expression Confers Resistance to Activation-Induced Cell Death in Regulatory T Cells

“…Although gld mice display elevated Treg numbers, the latter was unaltered in lpr mice (12,13). Moreover, several in vivo studies demonstrated that Treg numbers decline during an immune response as a result of CD95 ligation, whereas others claimed that CD95L expression by Tregs induces responder cell death in vitro (14)(15)(16)(17).…”