Lymph node fibroblastic reticular cells regulate differentiation and function of CD4 T cells via CD25

Lymph node fibroblastic reticular cells (LN-FRCs) provide functional structure to LNs and play important roles in interactions between T cells and antigen-presenting cells. However, the direct impact of LN-FRCs on naive CD4(+) T cell differentiation has not been explored. Here, we show that T cell zone FRCs of LNs (LN-TRCs) express CD25, the alpha chain of the IL-2 receptor heterotrimer. Moreover, LN-TRCs trans-present IL-2 to naive CD4(+) T cells through CD25, thereby facilitating early IL-2-mediated signaling. CD25-deficient LN-TRCs exhibit attenuated STAT5 phosphorylation in naive CD4(+) T cells during T cell differentiation, promoting T helper 17 (Th17) cell differentiation and Th17 response-related gene expression. In experimental autoimmune disease models, disease severity was elevated in mice lacking CD25 in LN-TRCs. Therefore, our results suggest that CD25 expression on LN-TRCs regulates CD4(+) T cell differentiation by modulating early IL-2 signaling of neighboring, naive CD4(+) T cells, influencing the overall properties of immune responses. Our findings demonstrate a previously unknown mechanism for the IL-2 receptor signaling mediated by LN-TRCs for differentiation of naive CD4 T cells. Particularly, reduced CD25 expression on the surface of LN-TRCs exacerbates autoimmune phenotypes through enhanced differentiation of Th17 cells.