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

Tor Henrik Anderson Tvedt; Stefan Rose-John; Galina Tsykunova; Aymen Bushra Ahmed; Tobias Gedde-Dahl; Elisabeth Ersvær; Øystein Bruserud

doi:10.3390/jcm11092530

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

J Clin Med. 2022 Apr 30;11(9):2530. doi: 10.3390/jcm11092530.

Authors

Tor Henrik Anderson Tvedt^{1

2

3}, Stefan Rose-John⁴, Galina Tsykunova³, Aymen Bushra Ahmed³, Tobias Gedde-Dahl^{1

5}, Elisabeth Ersvær⁶, Øystein Bruserud^{2

3}

Affiliations

¹ Department of Hematology, University of Oslo, 0424 Oslo, Norway.
² Section for Hematology, Institute of Clinical Science, University of Bergen, 5007 Bergen, Norway.
³ Section for Hematology, Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway.
⁴ Institute of Biochemistry, Kiel University, Olshausenstrasse 40, 24118 Kiel, Germany.
⁵ Institute of Clinical Medicine, University of Oslo, 0315 Oslo, Norway.
⁶ Department of Biomedical Laboratory Scientist Education, Western Norway University of Applied Sciences, 5063 Bergen, Norway.

Abstract

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; this responsiveness is modulated by antithymocyte globulin and differs between patients with and without previous acute GVHD. These observations suggest that allotransplant recipients will be heterogeneous with regard to the effects of post-transplant IL-6 targeting.

Keywords: STAT3; T cells; allogeneic stem cell transplantation; graft-versus-host disease; interleukin 6; mTOR.

Abstract

Grants and funding