Background: IL-21 is a T cell growth factor for and secreted by Th17 and T follicular helper (Tfh)-cells. This cytokine has a diverse effect on a broad range of immune cells. It regulates CD8+ T cell expansion and their effector functions, and is crucial for T cell-dependent B cell differentiation of antigen-activated B cells into antibody-producing plasma cells.  However, little is known about IL-21 mediated T and B cell responses in alloreactivity after organ transplantation.
Materials and Methods: First, we explored the actions of IL-21 in alloreactive T cell proliferation and cytotoxicity in mixed lymphocyte reactions. Second, to test the role of IL-21 producing Tfh cells in the regulation of B cells in an alloantigen-driven setting, we performed co-culture experiments of kidney transplant patient Tfh cells and B cells that were stimulated with donor antigen. Third, the effect of an aIL-21R blocking antibody on the early phase of allograft rejection was studied in a humanized skin transplantation model in mice reconstituted with human T and B cells.
Results: Alloactivated T and B cells highly express IL-21R. In the presence of IL-21, a marked increased proliferative response of alloactivated T cells was found. Also, the expanded CD8+ T cells had significant cytolytic functions, while blockade of the IL-21 route by an aIL-21R antagonist inhibited the proliferation of alloactivated T-cells. Next, we determined the role of IL-21 in T cell dependent B cell responses. Donor antigen stimulation of the co-cultured Tfh – B cells initiated expression of the activation markers ICOS and PD-1 on Tfh cells with a shift toward a mixed Tfh2 and Tfh17 phenotype. The alloantigen activated memory B cells underwent class switch recombination and differentiated toward IgM- and IgG-producing plasmablasts. Anti-IL-21R antagonists significantly inhibited B cell differentiation. Finally, in the humanized mouse skin transplant model, in mice treated with the aIL-21R antagonist reduced signs of alloreactivity were measured including significantly less CD4+ and CD8+ T and B cell infiltration and less expression of inflammatory markers Keratin 17 and Ki67.
Conclusion: These data show that comparing the effects of new IL-21-targeting therapeutics against the conventional immunosuppressants used in transplantation would be of considerable interest. Blockade of the IL-21 pathway may provide a new perspective for the treatment of T and B cell mediated allogeneic responses after organ transplantation.