IL-6 Responsiveness of CD4+ and CD8+ T Cells after Allogeneic Stem Cell Transplantation Differs between Patients and Is Associated with Previous Acute Graft versus Host Disease and Pretransplant Antithymocyte Globulin Therapy

Graft-versus-host disease (GVHD), one of the most common and serious complications after allogeneic stem cell transplantation, is mediated by allocative T cells. IL-6 mediates both pro- and anti-inflammatory effects and modulates T cell response through classical signaling and trans-signaling. We investigated the effects on the mTOR and JAK/STAT pathways after various types of IL-6 signaling for circulating T cells were derived from 31 allotransplant recipients 90 days post-transplant. Cells were stimulated with IL-6 alone, hyper-IL-6 (trans-signaling), IL-6+IL-6 receptor (IL-6R; classical + trans-signaling) and IL-6+IL-6R+soluble gp130-Fc (classical signaling), and flow cytometry was used to investigate the effects on phosphorylation of AKT (Thr308), mTOR (Ser2442), STAT3 (Ser727) and STAT3 (Tyr705). CD3⁺CD4⁺ and CD3⁺C8⁺ T cells responded to classical and trans IL-6 stimulation with increased STAT3 (Tyr705) phosphorylation; these responses were generally stronger for CD3⁺CD4⁺ cells. STAT3 (Tyr705) responses were stronger for patients with previous acute GVHD; CD3⁺CD4⁺ cells from GVHD patients showed an additional STAT3 (Ser727) response, whereas patients without acute GVHD showed additional mTOR (Ser2448) responses. Furthermore, treatment with antithymocyte globulin as a part of GVHD prophylaxis was associated with generally weaker STAT3 (Tyr705) responses and altered STAT3 (Ser727) responsiveness of CD3⁺CD4⁺ cells together with increased mTOR (Ser2448) responses for the CD3⁺CD8⁺ cells. Thus, early post-transplant CD3⁺CD4⁺ and CD3⁺ CD8⁺ T cell subsets differ in their IL-6 responsiveness; [...] GVHD. These observations suggest that allotransplant recipients will be heterogeneous with regard to the effects of post-transplant IL-6 targeting.