Interleukin-5 (IL-5) Therapy Prevents Allograft Rejection by Promoting CD4CD25 Ts2 Regulatory Cells That Are Antigen-Specific and Express IL-5 Receptor

CD4CD25Foxp3T cell population is heterogenous and contains three major sub-groups. First, thymus derived T regulatory cells (tTreg) that are naïve/resting. Second, activated/memory Treg that are produced by activation of tTreg by antigen and cytokines. Third, effector lineage CD4CD25T cells generated from CD4CD25 T cells' activation by antigen to transiently express CD25 and Foxp3. We have shown that freshly isolated CD4CD25T cells are activated by specific alloantigen and IL-4, not IL-2, to Ts2 cells that express the IL-5 receptor alpha. Ts2 cells are more potent than naïve/resting tTreg in suppressing specific alloimmunity. Here, we showed rIL-5 promoted further activation of Ts2 cells to Th2-like Treg, that expressed and , we studied the effects of rIL-5 treatment on Lewis heart allograft survival in F344 rats. Host CD4CD25T cells were assessed by FACS, in mixed lymphocyte culture and by RT-PCR to examine mRNA of Ts2 or Th2-like Treg markers. rIL-5 treatment given 7 days after transplantation reduced the severity of rejection and all grafts survived ≥60d whereas sham treated rats fully rejected by day 31 (p<0.01). Treatment with anti-CD25 or anti-IL-4 monoclonal antibody abolished the benefits of treatment with rIL-5 and accelerated rejection. After 10d treatment with rIL-5, hosts' CD4CD25 cells expressed more and responded to specific donor Lewis but not self. Enriched CD4CD25 cells from rIL-5 treated rats with allografts surviving >60 days proliferated to specific donor only when rIL-5 was present and did not proliferate to self or third party. These cells had more mRNA for molecules expressed by Th2-like Treg includin and These findings were consistent with IL-5 treatment preventing rejection by activation of Ts2 cells and Th2-like Treg.