Emerging Concepts Targeting Immune Checkpoints in Cancer and Autoimmunity

Keishi Fujio, Kazuhiko Yamamoto, Tomohisa Okamura

Regulatory T cells (Treg cells) play crucial roles in the induction of peripheral tolerance to self- and foreign-antigens. IL-10-producing regulatory T cells (IL-10-producing Treg cells) constitute a Treg cell subset characterized by the production of high amounts of IL-10, cytokine-mediated immunosuppressive capabilities, and independence of Foxp3 expression for their suppressive activity. In the past decade, identifying naturally occurring IL-10-producing Treg cells was difficult due to the lack of suitable surface markers. More recently, lymphocyte activation gene 3 (LAG-3) is a CD4 homologue that has been identified as a marker for IL-10-producing Treg cells. CD4(+)CD25(-)LAG3(+) T cells produce large amounts of IL-10 and suppress colitis in a mouse model. These CD4(+)CD25(-)LAG3(+) Treg cells also exhibit suppressive activity in murine models of lupus and humoral immunity in a TGF-β3-dependent manner. Moreover, the combined expression of LAG-3 and CD49b identifies IL-10-producing Treg cells in mice and humans more specifically. Recently, LAG-3 has gained more attention in the context of immune checkpoints because it believed to be related to T cell tolerance and exhausted T cells that infiltrate the tumor microenvironment. Tumors and the tumor microenvironment promote development of IL-10-producing Treg cells and foster tumor growth. This response might interfere with protective immune responses. Understanding LAG-3-expressing IL-10-producing Treg cells may contribute to the development of novel therapeutic strategies in immune-mediated diseases.