Exhausted T cells in cancer and chronic viral infection express distinctive patterns of genes, including sustained expression of programmed cell death protein 1 (PD-1). However, the regulation of gene expression in exhausted T cells is poorly understood. Here, we define the accessible chromatin landscape in exhausted CD8+ T cells and show that it is distinct from functional memory CD8+ T cells. Exhausted CD8+ T cells in humans and a mouse model of chronic viral infection acquire a state-specific epigenetic landscape organized into functional modules of enhancers. Genome editing shows that PD-1 expression is regulated in part by an exhaustion-specific enhancer that contains essential RAR, T-bet, and Sox3 motifs. Functional enhancer maps may offer targets for genome editing that alter gene expression preferentially in exhausted CD8+ T cells.

PTPN22, a protein tyrosine phosphatase expressed mainly in hematopoietic cells, has been linked to many autoimmune diseases. A C-to-T single nucleotide polymorphism (SNP) at position 1858 of human PTPN22 cDNA decreases the risk of Crohn’s disease. However, the function of PTPN22 and the mechanism by which this SNP reduces the risk of Crohn’s disease are poorly understood. We find that PTPN22 is expressed in macrophages. It suppresses M1 macrophage polarization and reciprocally promotes the expression of M2-associated genes. PTPN22-deficient mice develop severe colitis induced by dextran sulfate sodium, and their intestinal macrophages express higher levels of M1 genes but lower levels of M2-associated genes. Furthermore, the protective T allele of the C1858T SNP is associated with attenuated expression of inflammatory cytokines and a higher level of PTPN22 in human M1 macrophages. This T allele–associated aberrant expression of PTPN22 is partly attributed to an autoinhibition mechanism, in which PTPN22 suppresses its own expression in M1 but not M2 macrophages. Our data not only demonstrate a critical role of PTPN22 in regulating macrophage polarization but also provide a molecular explanation for the protective effect of the C1858T SNP in Crohn’s disease.

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E26 transformation-specific sequence 1 (Ets-1), the prototype of the ETS family of transcription factors, is critical for the expression of IL-2 by murine Th cells; however, its mechanism of action is still unclear. Here we show that Ets-1 is also essential for optimal production of IL-2 by primary human Th cells. Although Ets-1 negatively regulates the expression of Blimp1, a known suppressor of IL-2 expression, ablation of B lymphocyte-induced maturation protein 1 (Blimp1) does not rescue the expression of IL-2 by Ets-1-deficient Th cells. Instead, Ets-1 physically and functionally interacts with the nuclear factor of activated T-cells (NFAT) and is required for the recruitment of NFAT to the IL-2 promoter. In addition, Ets-1 is located in both the nucleus and cytoplasm of resting Th cells. Nuclear Ets-1 quickly exits the nucleus in response to calcium-dependent signals and competes with NFAT proteins for binding to protein components of noncoding RNA repressor of NFAT complex (NRON), which serves as a cytoplasmic trap for phosphorylated NFAT proteins. This nuclear exit of Ets-1 precedes rapid nuclear entry of NFAT and Ets-1 deficiency results in impaired nuclear entry, but not dephosphorylation, of NFAT proteins. Thus, Ets-1 promotes the expression of IL-2 by modulating the activity of NFAT.E 26 transformation-specific sequence 1 (Ets-1) is the founding member of the ETS family of transcription factors (1, 2); it is expressed mainly in lymphoid cells and plays multiple roles in regulating the development and function of these cells. Ets-1-deficient (KO) Th1 cells produce very little IL-2 (3). However, it is still unclear whether Ets-1 is also critical for the expression of IL-2 in human Th cells and how Ets-1 promotes the expression of IL-2.The transcriptional regulation of IL-2 has been characterized (4, 5). One of the positive regulators of IL-2 expression is the nuclear factor of activated T-cells (NFAT) family of transcription factors, which contains five members (6, 7). The promoter of the IL-2 gene contains five consensus binding sequences of NFAT (8). Deficiency of both NFATc1 and NFATc2 severely attenuates the expression of IL-2, confirming the critical role of NFATs in regulating IL-2 expression (9). In resting T cells, NFATs are phosphorylated and retained in cytoplasm by the NRON complex, which consists of a backbone of noncoding RNA called noncoding RNA repressor of NFAT (NRON) and several proteins, including Tnpo1, Iqgap1, chromosome segregation 1-like (Cse1l), protein phosphatase 2, regulatory subunit A, alpha (Ppp2r1a), and Psmd11 (10-12). The NRON complex serves as a cytoplasmic trap of NFAT. T-cell antigen receptor (TCR) signals and dephosphorylation of NFAT lead to the release of NFAT from the NRON complex. Free dephosphorylated NFAT is then translocated into the nucleus and transactivates IL-2 and many other genes. However, the detailed mechanism regulating the assembly/disassembly of the NRON complex and cytoplasmic/nuclear translocation of NFAT is still not fully understood.B lymphocyte-i...

The cover image of this issue consists of confocal images of c‐Maf localization in HEK293 T cells, taken from Lin et al. (pp. 1174–1184). In this article, the authors examine regulation of c‐Maf function by SUMOylation. The authors show that c‐Maf colocalizes with SUMO (small ubiquitin‐like modifier) ligases; SUMOylation attenuates c‐Maf transcriptional activity, and subsequently, IL‐4 expression.