IL4-induced gene 1 is secreted at the immune synapse and modulates TCR activation independently of its enzymatic activity

Abstract Amino‐acid catabolizing enzymes produced by mononuclear phagocytes play a central role in regulating the immune response. The mammalian phenylalanine‐catabolizing enzyme IL4‐induced gene 1 (IL4I1) inhibits effector T lymphocyte proliferation and facilitates regulatory T‐cell development. IL4I1 expression by macrophages of various human tumors may affect patient prognosis as it facilitates tumor escape from the T‐cell response in murine models. Its enzymatic activity appears to participate in its effects, but some actions of IL4I1 remain unclear. Here, we show that the presence of IL4I1 during T‐cell activation decreases early signaling events downstream of TCR stimulation, resulting in global T‐cell inhibition which is more pronounced when there is CD28 costimulation. Surprisingly, the enzymatic activity of IL4I1 is not involved. Focal secretion of IL4I1 into the immune synaptic cleft and its binding to CD3 + lymphocytes could be important in IL4I1 immunosuppressive mechanism of action.