*Purpose: Antibody-mediated lymphoablation is a common induction therapy in solid organ transplantation. However, memory T cells are resistant to depletion in many clinical settings, and rapidly undergo homeostatic proliferation in lymphopenic hosts. Interleukin-33 (IL-33) is an important alarmin that can be released by lymphoablation or as a result of transplant-associated injury. We previously reported that IL1RL1 gene expression (Interleukin 1 receptor-like 1 aka IL-33R or ST2) was upregulated on B cells in mouse heart allograft recipients treated with mATG (murine analog of anti-thymocyte globulin). The current study tested the role of IL-33/ST2 signaling in T cell reconstitution following mATG lymphoablation in heart allograft recipients.
*Methods: C57BL/6 (B6.WT), B6.IL-33^-/- and B6.ST2^-/- recipients were transplanted with BALB/c heart allografts and treated with mATG (1mg i.p. on d.0 and d.4). To test whether IL-33 is derived from a heart graft, the B6.WT or B6.IL-33^-/- heart grafts were transplanted to BALB/c recipients. The numbers of CD4⁺, CD8⁺ T cells, regulatory T cells (Treg), and B cells were evaluated by flow cytometry. ST2 gene and protein expression on recipient spleen T and B cells were measured by Real-time PCR and flow cytometry, respectively.
*Results: mATG lymphoablation in heart transplant recipients upregulated ST2 expression on both B and T cells. Following mATG treatment, CD8 ⁺T cell recovery in peripheral blood and spleen was significantly decreased in B6.ST2^-/- compared to B6.WT recipients. Consistent with compromised CD8⁺T cell reconstitution, heart allograft survival was prolonged in B6.ST2^-/- recipients (MST of > 60 d vs 16 d in B6.WT recipients). Notably, donor but not recipient IL-33 deficiency resulted in decreased T and B cell reconstitution compared to recipients of B6.WT heart allografts. These results show that injured graft cells are a critical source of proinflammatory IL-33 and uncover the novel role for IL-33 during rapid B cell reconstitution in this model.
*Conclusions: Our data identify IL-33 as a potential target for controlling the undesirable expansion of memory T cells following lymphoablation in transplant recipients and raise further questions on the role of this cytokine in lymphocyte homeostasis under pro-inflammatory conditions.

Yosuke Yamamoto

Lerner Research Institute, Cleveland Clinic

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