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The molecular mechanisms responsible for the high immunosuppressive capacity of [CD4.sup.+] Tregs in tumors are not well known. High-dimensional single-cell profiling of T cells from chemotherapy-naive individuals with non-small-cell lung cancer identified the transcription factor IRF4 as specifically expressed by a subset of intratumoral [CD4.sup.+] effector Tregs with superior suppressive activity. In contrast to the [IRF4.sup.-] counterparts, [IRF4.sup.+] Tregs expressed a vast array of suppressive molecules, and their presence correlated with multiple exhausted subpopulations of T cells. Integration of transcriptomic and epigenomic data revealed that IRF4, either alone or in combination with its partner BATF, directly controlled a molecular program responsible for immunosuppression in tumors. Accordingly, deletion of Irf4 exclusively in Tregs resulted in delayed tumor growth in mice while the abundance of IRF4+ Tregs correlated with poor prognosis in patients with multiple human cancers. Thus, a common mechanism underlies immunosuppression in the tumor microenvironment irrespective of the tumor type., Introduction Despite recent clinical breakthroughs in adoptive T cell transfer approaches and checkpoint blockade in treating hematopoietic and solid tumors, suppression of the antitumor immune response in the tumor microenvironment [...]

Regulatory T cells play an essential role in preventing fetal rejection by the maternal immune system. Here we show that, based on the expression of CCR5, regulatory T cells can be divided into a highly suppressive [CCR5.sup.+] and a far less suppressive [CCR5.sup.-] subpopulation, suggesting that the former represent the effector arm of regulatory T cells. Although regulatory T cells from [CCR5.sup.-/-] gene deletion mutants still suppress, they are less effective mediators of maternal-fetal tolerance. The accumulation of [CCR5.sup.+] regulatory T cells at this site appears to be enhanced by alloantigen. This finding is in stark contrast to the systemic expansion of regulatory T cells during pregnancy, which appears to be alloantigen-independent. The fact that [CCR5.sup.+] regulatory T cells preferentially accumulate in the gravid uterus and that expression of CCR5 on regulatory T cells can be induced by activation lead us to propose that CCR5 is responsible for the accumulation of those regulatory T cells that have been activated by paternal antigens. effector T cells | pregnancy | tolerance | chemokine receptor