CD103⁺ Dendritic Cells Suppress Th1 Alloimmunity by Modulating CD11b⁺ Antigen Presenting Cells via IL-10

Abstract

Purpose : Conventional dendritic cells (cDC) are critical for initiating T helper-1(Th1) alloimmunity post-corneal transplantation; however, the differential roles and molecular mechanisms of migratory CD103⁺ cDC and CD11b⁺ Ag-presenting cells (APC) subsets in Th1 alloimmunity have not been completely investigated. Herein, we examined the function of CD103⁺ DC in regulating CD11b⁺ APC-mediated anti-allograft Th1 immunity

Methods : High risk (HR) and low risk (LR) allogeneic corneal transplantation were performed using C57BL/6 mice as donors and BALB/c as hosts. On days 1,3,4,7,and 14 post-transplantation, CD103⁺CD11c⁺ DC, B220^-CD11b⁺MHC-II^high APC, CD4⁺CD25⁺FoxP3⁺ regulatory T cells (Treg), and CD4⁺IFN-g⁺ (Th1) cells, were assessed by flow cytometry in graft recipient mice. On day 14, CD103⁺ DC of LR graft recipients and CD11b⁺ APC of HR graft recipients were FACS-sorted, incubated, and assessed for production of IL-10 and IL-12 by ELISA. CD11b⁺ APC were co-cultured with syngeneic CD103⁺ DC, syngeneic and CD4⁺CD25^- T cells, and allogeneic corneal lysate. Anti-IL10R blocking antibody was added, and IL-12 and IFN-g were measured by ELISA in supernatants

Results : CD103⁺ DC frequencies were significantly higher in LR setting compared to HR (p<0.001). CD11b⁺MHC-II^high APC frequencies were found significantly augmented in the HR setting compared to LR (p<0.001). Funtional Treg (measured by FoxP3 expression) were found significantly higher in LR vs. HR (p<0.01), but no significant change in Treg-frequencies was observed. Th1 cell frequencies were significantly increased in HR vs. LR (p<0.001). IL-10 production was significantly reduced (p<0.001) and IL-12 significantly increased (p<0.001) by CD11b⁺ APC compared to CD103⁺ DC. The presence of CD103⁺ DC with CD11b APC led to a significant reduction in IL-12 secretion by CD11b⁺ APC (p<0.001) and modulation of allosensitization measured by IFN-g production by Th1 cells compared to CD11b⁺ DC alone (p<0.001). Blocking IL-10R, abrogated the modulatory effect of CD103⁺ DC on CD11b⁺ APC

Conclusions : These results provide novel insights into the distinct roles of migratory DC subsets in the regulation of Th1 immunity. Additionally, they show that CD103⁺ DC are critical for regulating Th1 immunity following corneal transplantation

This is a 2021 ARVO Annual Meeting abstract.