Recipient conditioning contributes to IL-33-driven Th1 alloimmune responses following rapid ST2 upregulation on donor CD4+ T cells during lymphopenia-induced proliferation

Abstract

Abstract IL-33 is augmented in recipient tissues by conditioning before allogeneic stem cell transplantation (alloSCT) and is a required signal to donor T cell for GVHD. Targetable mechanisms by which IL-33 supports GVHD are yet undefined. Conditioning causes lymphopenia-induced proliferation (LIP) and releases microbial products. These products promote myeloid cell secretion of IL-12, which induces the IL-33 receptor, ST2, on T cells in vitro. We hypothesized that IL-12 induces ST2 on donor T cells during LIP promoting IL-33 augmentation of the Th1 responses leading to GVHD. To establish the role of IL-12 in T cell ST2 expression and IL-33-mediated GVHD, irradiated BALB/c mice were given B6 alloSCT and T cells. Some mice received IL-12p40 neutralizing Ab or control Ab alone, with or without concurrent IL-33 administration. To test the impact of lymphopenia on T cells, ST2−Foxp3−CD4+ T cells alone or with ST2+ Treg were transferred into B6 Rag2−/−γc−/− mice. Mice received PBS or IL-33 on days 1–8. Neutralizing IL-12 did not reduce ST2 on T cells after alloSCT nor rescue mice from IL-33-mediated acceleration of GVHD. Post-alloSCT, IL-33 worked with IL-12 to expand ST2+Tbet+ Th1 cells. Neutralizing IL-12, but not delivery of IL-33, increased Gata3+ Th2 cells after alloSCT. During LIP, CD4+Foxp3− T cells rapidly upregulated ST2 independent of IL-33, but IL-33 then favored the expansion of Th1 cells, even in the presence of ST2+ Treg. These data suggest that CD4+ T cells rapidly upregulate ST2 during alloSCT conditioning induced lymphopenia. After alloSCT, IL-33 does not support Treg or Th2 cells, but works with IL-12 to augment Th1 responses and GVHD. Blocking stimuli that induces ST2 on proliferating donor CD4+ T cells may be effective for limiting GVHD.