Precocious Interleukin 21 Expression in Naive Mice Identifies a Natural Helper Cell Population in Autoimmune Disease

Interleukin 21 (IL-21) plays key roles in humoral immunity and autoimmune diseases. It is known to function in mature CD4⁺ T follicular B cell helper (T_FH) cells, but its potential involvement in early T cell ontogeny is unclear. Here, we find that a significant population of newly activated thymic and peripheral CD4⁺ T cells functionally expresses IL-21 soon after birth. This naturally occurring population, termed natural (n)T_H21 cells, exhibits considerable similarity to mature T_FH cells. nT_H21 cells originating and activated in the thymus are strictly dependent on autoimmune regulator (AIRE) and express high levels of NUR77, consistent with a bias toward self-reactivity. Their activation/expansion in the periphery requires gut microbiota and is held in check by FoxP3⁺ T_REG cells. nT_H21 cells are the major thymic and peripheral populations of IL-21⁺ cells to expand in an IL-21-dependent humoral autoimmune disease. These studies link IL-21 to T cell ontogeny, self-reactivity, and humoral autoimmunity.