MEDICINE AND HEALTH

Cathepsin W achieves homeostasis of mucosal immunity by controlling the proliferation and function of peripheral regulatory T cells


On July 12, 2023, the National Institutes of Health/National Cancer Institute Chuan Wu lab published a new paper titled “Cathepsin W restrains peripheral regulatory T cells for mucosal immune quiescence” online at Science Advances.

Regulatory T (Treg) cells play a key role in controlling immune tolerance and immune stability. Based on their origin, two different Treg cell subtypes have been identified, including thymic Treg (tTreg) cells and peripheral Treg (pTreg) cells. tTreg cells are known to develop in the thymus and recognize autoantigens, while pTreg cells, differentiated from first-time CD4+ T cells in peripheral organs, are critical for mucosal immunohomeostasis at the barrier surface. Previous studies have shown that both tTreg and pTreg cell production require T cell receptor (TCR) stimulation and cytokine signaling, such as interleukin 2 (IL-2). Activation of downstream STAT5 by IL-2 signaling contributes to Foxp3 expression and Treg cell development.

IL-2 binds with high affinity to the IL-2 receptor (IL-2R), which consists of the IL-2 receptor A chain (IL-2Ra, CD25), the common γ chain (γc, CD132), and IL-2Rβ (CD122). Previous studies have revealed that IL-2R plays a key role in tTreg and pTreg cell production, maintenance, and expansion by stabilizing Foxp3 expression. In addition, IL-2R signaling has been shown to promote the inhibitory function of Treg cells by activating STAT5. As one of the most abundantly expressed IL-2R subunits on Treg cells, CD25 has been shown to be co-expressed with Foxp3 in naïve CD4+ T cells. Therefore, CD25 can be used as a surface marker for Treg cells, which is also considered indispensable in Treg cell development. In addition, CD25 expression has been shown to contribute to the stable expression of Foxp3 and the inhibitory function of Treg in Treg cells. Loss of CD25 leads to impaired Treg cell function, leading to impaired immune tolerance, leading to autoimmune disease. However, CD25 expression on Treg cells can vary depending on the activation state of Treg cells and the surrounding tissue environment. Although Foxp3 is known to directly promote CD25 transcription, the molecular mechanisms by which CD25 protein levels are regulated to influence Treg cell production and development remain unclear.

Illustration: (A) Ctsw is specifically induced by TGF-b. CTSW inhibits the last expression of IL-2R on the membrane surface by interacting with and cleaving CD25 within the cytoplasm, thereby limiting the activation of STAT5 and the expression of Foxp3. (B) CTSW-deficient T cells protect mice from T-cell-induced colitis by increasing the production and stabilization of Treg cells in the gut.

Cathepsin W (CTSW) is a member of the cysteine protease family. Most cathepsin are present in antigen-presenting cells and involved in antigen processing. Previous studies have shown that CTSW is present in CD8+ T cells and natural killer (NK) cells, but its role in controlling the immune response has not been clearly elucidated. In the current study, through transcriptomic and proteomic analysis, we found that CTSW is highly expressed in pTreg cells in the presence of TGF-b, which plays an important role in inhibiting pTreg cell differentiation and function. CTSW deletion leads to increased Foxp3 expression and enhanced inhibitory function during pTreg cell differentiation. CTSW deficiency also results in an increase in pTreg cells on the mucosal surface of the gastrointestinal tract (GI) in the body. Mechanistically, we demonstrate that CTSW participates in the processing of IL-2R in the cytoplasm by interacting with CD25 and cleaving CD25. In turn, CTSW limits STAT5 activation under IL-2 signaling, thereby inhibiting Foxp3 expression and pTreg cell function. Therefore, we elucidate the negative regulatory mechanism that limits pTreg cell production by inhibiting IL-2R signaling by CTSW, thereby regulating the mucosal immune balance of the intestine.

Jian Li, the co-first author of the paper, is a postdoctoral fellow in Wu Chuan’s laboratory, and Professor Wu Chuan is the corresponding author. (Source: Science Network)

Related paper information:https://www.science.org/doi/10.1126/sciadv.adf3924



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