Date: Saturday, June 2, 2018
Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Hall 4EF
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–CD44loST2lo 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).
To cite this abstract in AMA style: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 [abstract]. https://atcmeetingabstracts.com/abstract/recipient-conditioning-results-in-il-33-support-of-potent-th1-alloimmune-responses-after-cd4-t-cells-upregulate-st2-during-lymphopenia-induced-proliferation/. Accessed January 25, 2021.
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