Purpose: IL-33 is typically associated with support of Th2 and Treg responses. Yet, recipient conditioning before allogeneic hematopoietic cell transplantation (alloHCT) releases IL-33 to promote Th1 alloimmunity and graft vs. host disease (GVHD). IL-33-mediated GVHD immunopathology involves direct stimulation of donor T cells, yet the mechanisms mediating IL-33 support of GVHD are unclear. Conditioning releases self and bacteria materials that promote myeloid cell secretion of IL-12. IL-12 induces the IL-33 receptor, ST2, on T cells in vitro. We tested the hypothesis that neutralizing IL-12 post alloHCT would block IL-33 support of donor ST2⁺ Th1 responses and limit GVHD.

Methods: To establish the role of IL-12 in T cell ST2 upregulation and IL-33-mediated GVHD responses, irradiated BALB/c recipients were given 1×10⁷ B6 BM with 2×10⁶ B6 T cells. Some cohorts received IL-12p40 neutralizing Ab or control Ab alone, or with IL-33 (d3-7). Survival was determined. Splenocytes were assessed at d7. B6 Rag2^-/-γc^-/- mice were used to test the impact of IL-33 on CD4⁺ T cells in lymphopenic conditions. Mice were infused with 5×10⁴ CD90.1⁺CD4⁺ST2⁺ Treg and 4.5×10⁵ CD90.2⁺CD4⁺Foxp3^–CD44^loST2^lo T cells and received PBS or IL-33 on day (d)1-8. Splenocytes were assessed by flow cytometry on d9.

Results: During lymphopenia-induced proliferation, CD4⁺Foxp3^– T cells rapidly upregulate ST2. IL-33 favored the expansion of non-Treg cells, even in the presence of ST2⁺ Treg. Post-alloHCT, IL-33 worked with IL-12 to expand ST2⁺Tbet⁺ Th1 cells. Only neutralization of IL-12, but not delivery of IL-33, increased Gata3⁺Th2 cells or Treg. Therapeutic doses of anti-IL-12p40 did not reduce ST2⁺ T cells nor rescue mice from IL-33-mediated acceleration of GVHD.

Conclusion: CD4⁺ T cells transferred into the lymphopenic environments rapidly upregulate ST2 and are expanded by IL-33. After alloHCT, released IL-33 does not facilitate ST2⁺ Treg or ST2⁺Gata3⁺ Th2 cells, but works with IL-12 to profoundly augment ST2⁺Tbet⁺Th1 responses. That anti-IL-12 did not provide protection suggests that IL-33 may mediate GVHD lethality independent of IL-12. Identification of the stimuli that drives ST2 expression on proliferating CD4⁺ T cells will be critical to limit the detrimental functions of IL-33 after alloHCT.

CITATION INFORMATION: Dwyer G., Mathews L., Lucas A., Blazar B., Turnquist H. Recipient Conditioning Results in IL-33 Support of Potent Th1 Alloimmune Responses after CD4⁺ T Cells Upregulate ST2 during Lymphopenia Induced Proliferation Am J Transplant. 2017;17 (suppl 3).

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