Trafficking between clonally related peripheral T helper cells and tissue-resident T helper cells in chronic GVHD.

Chronic graft versus host disease (cGVHD) is an autoimmune-like syndrome. CXCR5-PD-1hi peripheral T helper (Tph) cells have an important pathogenic role in autoimmune diseases, but the role of Tph cells in cGVHD remains unknown. Here, we show that in cGVHD patients, expansion of Tph cells among blood CD4+ T cells was associated with cGVHD severity. These cells augmented memory B cell differentiation and production of IgG via IL-21. Tph cell expansion was also observed in murine model of cGVHD. This Tph expansion in the blood is associated with the expansion of pathogenic tissue-resident T helper (Trh) cells that form lymphoid aggregates surrounded by collagen in GVHD target tissues. Adoptive transfer experiments showed that Trh cells from GVHD target tissues give rise to Tph cells in the blood, and conversely, Tph cells from the blood give rise to Trh cells in GVHD target tissues. Tph cells in the blood and Trh cells in GVHD target tissues had highly overlapping T cell receptor α and β repertoires. Deficiency of IL-21R, BCL6, or T-bet in donor T cells markedly reduced the proportions of Tph cells in the blood and Trh cells in GVHD target tissues and reduced T-B interaction in the lymphoid aggregates. These results indicate that clonally related pathogenic Tph cells and Trh cells traffic between the blood and chronic GVHD target tissues, and that IL-21R-BCL6 signaling and T-bet are required for the development and expansion of Tph and Trh cells in the pathogenesis of cGVHD.