SUMMARY
Upon infection, CD8+ T cells undergo a stepwise process of early activation, expansion and differentiation into effector cells. How these phases are transcriptionally regulated is incompletely defined. Here, we report that interferon regulatory factor 4 (IRF4), dispensable for early CD8+ T cell activation, was vital for sustaining the expansion and effector differentiation of CD8+ T cells. Mechanistically, IRF4 promoted the expression and function of Blimp1 and T-bet, two transcription factors required for CD8+ T cell effector differentiation, while repressed genes that mediate cell cycle arrest and apoptosis. Selective ablation of Irf4 in peripheral CD8+ T cells impaired anti-viral CD8+ T cell responses, viral clearance and CD8+ T cell-mediated host recovery from influenza infection. IRF4 expression was regulated by T cell receptor (TCR) signaling strength via mammalian target of rapamycin (mTOR). Our data reveal that IRF4 translates differential strength of TCR-signaling into different quantitative and qualitative CD8+ T cell responses.
T helper cell effector subsets develop in response to specific cytokine environments. The development of a particular cytokine-secreting pattern requires an integration of signals that may promote the development of opposing pathways. A recent example of this paradigm is the IL-9-secreting Th9 cell that develops in response to TGFβ and IL-4, cytokines that in isolation promote the development of iTregs and Th2 cells, respectively. To determine how the balance of these factors results in priming for IL-9 secretion, we examined the effects of each pathway on transcription factors that regulate T helper cell differentiation. We demonstrate that TGFβ induces the PU.1-encoding Sfpi1 locus and that this is independent of IL-4-induced STAT6 activation. IL-4-activated STAT6 is required for repressing the expression of T-bet and Foxp3 in Th9 cells, transcription factors that inhibit IL-9 production, and is required for the induction of IRF4, which promotes Th9 development. These data establish a transcription factor network that regulates IL-9, and demonstrates how combinationsof cytokine signals generate cytokine-secreting potential by altering the expression of a panel of transcription factors.
In response to infection, naïve CD4 T cells differentiate into two subpopulations: T follicular helper (T) cells, which support B cell antibody production, and non-T cells, which enhance innate immune cell functions. Interleukin-2 (IL-2), the major cytokine produced by naïve T cells, plays an important role in the developmental divergence of these populations. However, the relationship between IL-2 production and fate determination remains unclear. Using reporter mice, we found that differential production of IL-2 by naïve CD4 T cells defined precursors fated for different immune functions. IL-2 producers, which were fated to become T cells, delivered IL-2 to nonproducers destined to become non-T cells. Because IL-2 production was limited to cells receiving the strongest T cell receptor (TCR) signals, a direct link between TCR-signal strength, IL-2 production, and T cell fate determination has been established.
Signal Transducer and Activator of Transcription (STAT) family members direct the differentiation of T helper cells, with specific STAT proteins promoting distinct effector subsets. STAT6 is required for the development of T helper 2 (Th2) cells, whereas STAT3 promotes differentiation of Th17 and follicular helper T cell subsets. We demonstrated that STAT3 was also activated during Th2 cell development and was required for the expression of Th2-cell associated cytokines and transcription factors. STAT3 bound directly to Th2-cell associated gene loci and was required for the ability of STAT6 to bind target genes. In vivo, STAT3-deficiency in T cells eliminated the allergic inflammation in mice sensitized and challenged with ovalbumin, or transgenic for constitutively active STAT6. Thus, STAT3 cooperates with STAT6 in promoting Th2 cell development. These results demonstrate that differentiating T helper cells integrate multiple STAT protein signals during Th2 cell development.
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