T Cell-Specific Deficiency of Src Homology 2-Containing Protein Tyrosine Phosphatase 2 Ameliorates Psoriasis and...

Psoriasis and ulcerative colitis are both autoimmune diseases with complex pathogenesis characterized by immune disorders. Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) is a non-receptor protein tyrosine phosphatase that acts as a key regulator of immune cell-mediated inflammation. Although studies have described the role of SHP2 in autoimmune diseases, its influence on the development of regulatory T cells (Tregs) was undefined, which plays a critical role in immune homeostasis. Here, we found that imiquimod (IMQ)-induced psoriasis symptoms were milder in Lck-Cre;SHP2^f/f mice than those in SHP2^f/f mice, including reduced inflammatory cell infiltration and keratinocyte proliferation. The reduced Th17/Treg ratio in psoriasis models in Lck-Cre;SHP2^f/f mice suggests that SHP2 regulates the balance of Th17/Treg. In vitro, the deficiency of SHP2 promotes the differentiation of T cells into Tregs. In the model of adoptive transfer colitis, the SHP2-deficient CD4⁺CD25^-CD45RB^high T cells differentiated into a greater number of Tregs within the recipient mice, resulting in attenuated symptoms of colitis. Moreover, cotransfer experiments confirmed that the deficiency of SHP2 does not affect the immunosuppressive function of Tregs. These findings establish that SHP2 reduces Treg differentiation and further confirm that SHP2 inhibitors could be utilized in the treatment of autoimmune diseases.