Cathepsin W restrains peripheral regulatory T cells for mucosal immune quiescence

Abstract

Peripheral regulatory T (pT reg ) cells are a key T cell lineage for mucosal immune tolerance and anti-inflammatory responses, and interleukin-2 receptor (IL-2R) signaling is critical for T reg cell generation, expansion, and maintenance. The expression of IL-2R on pT reg cells is tightly regulated to ensure proper induction and function of pT reg cells without a clear molecular mechanism. We here demonstrate that Cathepsin W (CTSW), a cysteine proteinase highly induced in pT reg cells under transforming growth factor–β stimulation is essential for the restraint of pT reg cell differentiation in an intrinsic manner. Loss of CTSW results in elevated pT reg cell generation, protecting the animals from intestinal inflammation. Mechanistically, CTSW inhibits IL-2R signaling in pT reg cells by cytosolic interaction with and process of CD25, repressing signal transducer and activator of transcription 5 activation to restrain pT reg cell generation and maintenance. Hence, our data indicate that CTSW acts as a gatekeeper to calibrate pT reg cell differentiation and function for mucosal immune quiescence.