A Subset of Interleukin-21⁺ Chemokine Receptor CCR9⁺ T Helper Cells Target Accessory Organs of the Digestive System in Autoimmunity

This study describes a CD4⁺ T helper (Th) cell subset marked by coexpression of the cytokine interleukin 21 (IL-21) and the gut-homing chemokine receptor CCR9. Although CCR9⁺ Th cells were observed in healthy mice and humans, they were enriched in the inflamed pancreas and salivary glands of NOD mice and in the circulation of Sjögren's syndrome patients. CCR9⁺ Th cells expressed large amounts of IL-21, inducible T cell costimulator (ICOS), and the transcription factors Bcl6 and Maf, and also supported antibody production from B cells, thereby resembling T follicular B helper (Tfh) cells. However, in contrast to Tfh cells, CCR9⁺ Th cells displayed limited expression of CXCR5 and the targets of CCR9⁺ Th cells were CD8⁺ T cells whose responsiveness to IL-21 was necessary for the development of diabetes. Thus, CCR9⁺ Th cells are a subset of IL-21-producing T helper cells that influence regional specification of autoimmune diseases that affect accessory organs of the digestive system.