Expression of co-inhibitory receptors, such as CTLA-4 and PD-1, on effector T cells is a key mechanism for ensuring immune homeostasis. Dysregulated co-inhibitory receptor expression on CD4+ T cells promotes autoimmunity while sustained overexpression on CD8+ T cells promotes T cell dysfunction or exhaustion, leading to impaired ability to clear chronic viral infections and cancer1,2. Here, we used RNA and protein expression profiling at single-cell resolution to identify a module of co-inhibitory receptors that includes not only several known co-inhibitory receptors (PD-1, Tim-3, Lag-3, and TIGIT), but also a number of novel surface receptors. We functionally validated two novel co-inhibitory receptors, Activated protein C receptor (Procr) and Podoplanin (Pdpn). The module of co-inhibitory receptors is co-expressed in both CD4+ and CD8+ T cells and is part of a larger co-inhibitory gene program that is shared by non-responsive T cells in multiple physiological contexts and is driven by the immunoregulatory cytokine IL-27. Computational analysis identified the transcription factors Prdm1 and c-Maf as cooperative regulators of the co-inhibitory module, which we validated experimentally. This molecular circuit underlies the co-expression of co-inhibitory receptors in T cells and identifies novel regulators of T cell function with the potential to regulate autoimmunity and tumor immunity.

Obesity is an epidemic in much of the developed world, for example in the United States, with 20% of males and 25% of females now classified as obese (Body Mass Index (BMI) ≥ 30.0 kg/m 2 ). 1On the other hand, in Japan, the prevalence of preobese (BMI: 25.0-29.9 kg/m 2 ) and obese (BMI ≥ 30.0 kg/m 2 ) men increased from 14.5% and 0.8%, respectively, in the time-period 1976-80 to 20.5% and 2.01% during 1991-95, and obesity has increased gradually among Japanese people, who are generally shorter and

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