Tc17 cells mediate gut GVHD via IL-22 and dysbiosis

Gut GVHD is critical for determining the outcome of allogenic hematopoietic cell transplantation (HCT). Damage of Paneth cells and loss of RegIIIg can lead to dysregulation of intestinal microbiota and gut GVHD pathogenesis. RegIIIg can be produced by Paneth cells and intestinal epithelial cells, and its secretion is augmented by IL-22. However, the circumstances leading to RegIIIg dysregulation and dysbiosis remain largely unknown. Here we show that, in a MHC-mismatched model of C57BL/6 donor to BALB/c recipient, one injection of depleting anti-CD4 effectively prevents acute gut GVHD in recipients given wild-type (WT) transplants but has no effect in recipients given IFN-g−/− transplants. Interestingly, PD-L1−/−recipients given IFN-g−/− transplants showed spontaneous recovery of the disease. Recipients given IFN-g−/− transplants showed expansion of Tc17, IL-22 but not IL-17 from Tc17 was required for the disease induction. Furthermore, host tissue PD-L1 augmented expansion of Tc17 as well as CX3CR1+ DC, CX3CR1+ DC mediate bacteria clearance and prevent bacteria translocation, at the same time, CX3CR1+ DC produce IL-18 BP, which limit Tc17 expansion through IL-18 signaling. In addition, recipients given IFN-g−/− transplants showed no damage of Paneth cells but markedly increased RegIIIg. Gut GVHD in recipients had significant reduction of Barnesiella in feces and significant increase of E. Coli and Lactobacillus. Taken together, these results indicate that 1) in the absence of donor IFN-g, host-tissue PD-L1 mediates expansion of Tc17 through IL-18 signaling and dysregulation of IL-22 functional effect; 2) Dysregualtion of IL-22 from Tc17 cell can lead to dysbiosis and gut GVHD in the absence of Paneth cell damage.