Monoclonal T Cells Identified in Early NOD Islet Infiltrates

AbstractTo examine the hypothesis that a single initiating antigen was recognized by a monoclonal T cell population leading to subsequent inflammatory insulitis in nonobese (NOD) mouse islets, we examined the T cell receptor (TCR) Vβ repertoire of islet-infiltrating T cells in very young (2-week-old) NOD mice. In independent experiments, we repeatedly identified one monoclonal TCR Vβ8.2 gene product expressed by T lymphocytes infiltrating the islets of NOD mice at 2 weeks of age. The resultant inflammatory response quickly obscures the monoclonal nature of the initiating event. These data suggest that autoimmune diabetes in NOD mice may be initiated by recognition of a single autoantigen

GRAIL An E3 Ubiquitin Ligase that Inhibits Cytokine Gene Transcription Is Expressed in Anergic CD4+ T Cells

AbstractT cell anergy may serve to limit autoreactive T cell responses. We examined early changes in gene expression after antigen-TCR signaling in the presence (activation) or absence (anergy) of B7 costimulation. Induced expression of GRAIL (gene related to anergy in lymphocytes) was observed in anergic CD4+ T cells. GRAIL is a type I transmembrane protein that localizes to the endocytic pathway and bears homology to RING zinc-finger proteins. Ubiquitination studies in vitro support GRAIL function as an E3 ubiquitin ligase. Expression of GRAIL in retrovirally transduced T cell hybridomas dramatically limits activation-induced IL-2 and IL-4 production. Additional studies suggest that GRAIL E3 ubiquitin ligase activity and intact endocytic trafficking are critical for cytokine transcriptional regulation. Expression of GRAIL after an anergizing stimulus may result in ubiquitin-mediated regulation of proteins essential for mitogenic cytokine expression, thus positioning GRAIL as a key player in the induction of the anergic phenotype

Essential Role of the E3 Ubiquitin Ligase Cbl-b in T Cell Anergy Induction

AbstractAntigen-specific immunotolerance limits the expansion of self-reactive T cells involved in autoimmune diseases. Here, we show that the E3 ubiquitin ligase Cbl-b is upregulated in T cells after tolerizing signals. Loss of Cbl-b in mice results in impaired induction of T cell tolerance both in vitro and in vivo. Importantly, rechallenge of Cbl-b mutant mice with the tolerizing antigen results in massive lethality. Moreover, ablation of Cbl-b resulted in exacerbated autoimmunity. Mechanistically, loss of Cbl-b rescues reduced calcium mobilization of anergic T cells, which was attributed to Cbl-b-mediated regulation of PLCγ-1 phosphorylation. Our results show a critical role for Cbl-b in the regulation of peripheral tolerance and anergy of T cells

A Novel Transcription Factor, T-bet, Directs Th1 Lineage Commitment

AbstractNaive T helper cells differentiate into two subsets, Th1 and Th2, each with distinct functions and cytokine profiles. Here, we report the isolation of T-bet, a Th1-specific T box transcription factor that controls the expression of the hallmark Th1 cytokine, IFNγ. T-bet expression correlates with IFNγ expression in Th1 and NK cells. Ectopic expression of T-bet both transactivates the IFNγ gene and induces endogenous IFNγ production. Remarkably, retroviral gene transduction of T-bet into polarized Th2 and Tc2 primary T cells redirects them into Th1 and Tc1 cells, respectively, as evidenced by the simultaneous induction of IFNγ and repression of IL-4 and IL-5. Thus, T-bet initiates Th1 lineage development from naive Thp cells both by activating Th1 genetic programs and by repressing the opposing Th2 programs