IL-33 is a critical early activation and differentiation signal for alloreactive CD4+ T cells that enables their infiltration into GVHD target tissues

Le résumé fourni par la source

Abstract Graft vs host disease (GVHD) is a lethal complication after allogeneic stem cell transplantation (alloSCT), where donor T cells destroy host tissues. To create space for donor cells and prevent their rejection, alloSCT protocols use recipient conditioning that augments the stromal-derived cytokine interleukin (IL)-33 in the lymphoid organs (LO) and tissues. While we have established that IL-33 is a clinically-relevant signal in GVHD, mechanisms by which it contributes to alloimmunity are not well defined. Herein, we used IL-33 receptor, ST2, deficient B6 mice as T cell donors to elucidated IL-33-mediated mechanisms in the early activation and differentiation of alloreactive T cells. In our model, we transferred equal ratios of B6 Cd4-Cre x St2fl/fl (ST2ko) and Cd4-Cre (ST2wt) donor T cells into irradiated B6 and BALB/c recipients. Donor T cells in the LO and tissues were characterized at day 1–3, 5, and 7 post alloSCT. BALB/c recipients exhibited blunted early activation and proliferation of alloresponsive ST2ko CD4+ T cells compared to ST2wt CD4+ T cells in LO of the same recipient. ST2ko T cells in allogeneic recipients also failed to differentiation into Tbethi and CXCR3hi Th1 cells able to infiltrate into target tissues and cause GVHD. RNAseq analysis confirmed the need for IL-33-signaling for alloreactive Th1 generation as ST2KO CD4+ cells exhibited reduced IFNγ, Tbet, CXCR3, and instead expressed higher levels of Th2 and regulatory molecules (Foxp3, IL10, Gata3). IL-33 signaling was not required for the non-alloantigen driven lymphopenic expansion by CD4+ T cells in syngeneic recipients. These data establish a previously unappreciated and targetable role for IL-33 in effective alloAg-reactive donor Th1 generation after alloSCT.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.