Extrafollicular CD4(+) T-B interactions are sufficient for inducing autoimmune-like chronic graft-versus-host disease

Chronic graft-versus-host disease (cGVHD) is an autoimmune-like syndrome mediated by pathogenic CD4(+) T and B cells, but the function of extrafollicular and germinal center CD4(+) T and B interactions in cGVHD pathogenesis remains largely unknown. Here we show that extrafollicular CD4(+) T and B interactions are sufficient for inducing cGVHD, while germinal center formation is dispensable. The pathogenesis of cGVHD is associated with the expansion of extrafollicular CD44(hi)CD62(lo)PSGL-1(lo)CD4(+) (PSGL-1(lo)CD4(+)) T cells. These cells express high levels of ICOS, and the blockade of ICOS/ICOSL interaction prevents their expansion and ameliorates cGVHD. Expansion of PSGL-1(lo)CD4(+) T cells is also prevented by BCL6 or Stat3 deficiency in donor CD4(+) T cells, with the induction of cGVHD ameliorated by BCL6 deficiency and completely suppressed by Stat3 deficiency in donor CD4(+) T cells. These results support that Stat3- and BCL6-dependent extrafollicular CD4(+) T and B interactions play critical functions in the pathogenesis of cGVHD.