Tim-3 drives tissue Treg effector function to promote neonatal immune tolerance and tumor-induced immune suppression
Tissue regulatory T cells (Treg) are a key player in preventing immune pathology and shaping the immune suppressive tumor microenvironment (TME). The signaling molecules that uniquely regulate tissue Treg are not well understood. Here, we show that Tim-3 was predominantly expressed in Treg cells in both normal and tumor tissues. Notably, Tim-3 deficiency in Tregs led to the development of severe signs of autoimmune diseases in neonatal mice, indicating a crucial role of Tim-3 in establishing immune tolerance in early life. In addition, deletion of Tim-3 on Tregs resulted in reduced numbers and suppressor activities of tumoral Tregs and an increase in antitumor immune responses. A gene profiling study revealed the requirement of Tim-3 in upregulation of effector Treg genes encoding immune inhibitory molecules, chemokine receptors for tissue residency, chemokines, and cytokines. Moreover, Tim-3 deficiency in Tregs and treatment with PD-1 mAbs synergistically inhibited tumor growth. Our study demonstrates the essential role of Tim-3 in driving tissue effector Treg-mediated immune suppression.
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