IL4I1: Key immunoregulator at a crossroads of divergent T-cell functions.

Abstract

The interleukin (IL)-4-induced gene1 (IL4I1), which encodes the L-amino acid oxidase enzyme, plays an important immunoregulatory role. Indeed, this enzyme which is produced by B cells-including neoplastic B cells-dendritic cells and macrophages has been shown to inhibit proliferation, cytotoxicity and IFN-γ production by tumor-infiltrating CD8+ T cells, thus favoring tumor escape. Moreover, the same gene has been found to be constitutively expressed by CD4+ T helper 17 (Th17) cells, where it down-regulates cell proliferation through a reduction of CD3 chains expression in the T-cell receptor complex, thus impairing IL-2 production, and by maintaining in the same cells a high expression of Tob1, which inhibits cell cycle entry, through a still unknown mechanism. Finally, IL4I1 has been shown to drive the differentiation of naive T cells into inducible regulatory T (iTreg) cells. Taken together, IL4I1 down-regulates the effector CD8+ T-cell response, promotes the development of iTreg cells and limits the expansion of Th17 cells, thus not only favoring tumor escape, but also reducing the potentially dangerous effects of adaptive immune responses in chronic inflammatory disorders.