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 (TFH) 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)TH21 cells, exhibits considerable similarity to mature TFH cells. nTH21 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+ TREG cells. nTH21 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. [Display omitted] •Naturally occurring, activated CD4+ T cells that precociously express interleukin 21•Show hallmarks of prototypical follicular T helper cells•Thymic selection, requiring AIRE, is greatly increased with autoreactive TCR•Disproportionately increased with autoimmunity Marnik et al. identify a population of activated T cells that precociously express the cytokine interleukin 21. These naturally occurring cells develop within the thymus and periphery and are greatly elevated under autoimmune conditions. Thus, they may be critical contributors to the development of humoral autoimmunity.