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-1(hi) peripheral T-helper (Tph) cells have an important pathogenic role in autoimmune diseases, but the role of Tph cells in cGVHD remains unknown. We show that in patients with cGVHD, expansion of Tph cells among blood CD4(+) T cells was associated with cGVHD severity. These cells augmented memory B-cell differentiation and production of immunoglobulin G via interleukin 21 (IL-21). Tph cell expansion was also observed in a murine model of cGVHD. This Tph cell 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 graft-versus-host disease (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 alpha and beta repertoires. Deficiency of IL-21R, B-cell lymphoma 6 (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 cGVHD 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.

Automated summary

Expansion of CXCR5-PD-1(hi) peripheral T-helper (Tph) cells in patients with chronic graft-versus-host disease (cGVHD) is associated with disease severity. These cells promote memory B-cell differentiation and immunoglobulin G production through interleukin 21 (IL-21). Tph cells in the blood and tissue-resident T-helper (Trh) cells in cGVHD target tissues share T-cell receptor alpha and beta repertoires, and their trafficking between the blood and target tissues is controlled by IL-21R-BCL6 signaling and T-bet. The development and expansion of Tph and Trh cells are important in the pathogenesis of cGVHD.