IL-17 Gene Ablation Does Not Impact Treg-Mediated Suppression of Graft-Versus-Host Disease after Bone Marrow Transplantation

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• 作者：Lucrezia Colonna ; Mareike Florek ; Dennis B. Leveson-Gower ; Emanuela I. Sega ; Jeanette Baker ; Aaron T. Smith ; Robert S. Negrin
• 关键词：Regulatory T cells ; Graft-versus-host disease ; Th17 cells ; Bone marrow transplantation ; Allogeneic hematopoietic cell transplantation ; In vivo bioluminescence
• 刊名：Biology of Blood and Marrow Transplantation
• 出版年：November, 2013
• 年：2013
• 卷：19
• 期：11
• 页码：1557-1565
• 全文大小：1129 K

文摘

Regulatory T cell (Treg) immunotherapy is a promising strategy for the treatment of graft rejection responses and autoimmune disorders. Our and other laboratories have shown that the transfer of highly purified CD4⁺CD25⁺Foxp3⁺ natural Treg can prevent lethal graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation across both major and minor histocompatibility barriers. However, recent evidence suggests that the Treg suppressive phenotype can become unstable, a phenomenon that can culminate in Treg conversion into IL-17-producing cells. We hypothesized that the intense proinflammatory signals released during an ongoing alloreaction might redirect a fraction of the transferred Treg to the Th17 cell fate, thereby losing immunosuppressive potential. We therefore sought to evaluate the impact of Il17 gene ablation on Treg stability and immunosuppressive capacity in a major MHC mismatch model. We show that although Il17 gene ablation results in a mildly enhanced Treg immunosuppressive ability in聽vitro, such improvement is not observed when IL-17-deficient Treg are used for GVHD suppression in聽vivo. Similarly, when we selectively blocked IL-1 signaling in Treg, that was shown to be necessary for Th17 conversion, we did not detect any improvement on Treg_-mediated GVHD suppressive ability in聽vivo. Furthermore, upon ex聽vivo reisolation of transferred wild-type Treg, we detected little or no Treg_-mediated IL-17 production upon GVHD induction. Our results indicate that blocking Th17 conversion does not affect the GVHD suppressive ability of highly purified natural Treg in聽vivo, suggesting that IL-17 targeting is not a valuable strategy to improve Treg immunotherapy after hematopoietic cell transplantation.