IL-4-producing CD8+ T cells may be an immunological hallmark of chronic GVHD

Abstract

Summary:Chronic graft-versus-host disease (cGVHD) occurs in approximately 60-80% of those who survive over 100 days after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the pathophysiology of cGVHD is poorly understood. To gain more insight into the immunological mechanism of cGVHD, we examine cytokine production of peripheral blood T cells from 19 patients in the chronic phase of allo-HSCT. The percentage of IFN-c-producing CD8 þ T cells among CD8 þ T cells was significantly higher in patients with or without cGVHD than in normal control subjects (Po0.001). On the other hand, the percentage of IL-4-producing CD8 þ T cells among CD8 þ T cells was significantly higher in patients with cGVHD (mean 3.3%; range 1.3-8.2%) than in patients without cGVHD (mean 1.2%; range 0.8-1.7%) and normal control subjects (mean 1.1%; range 0.1-1.6%) (both Po0.001). By contrast, the percentage of IL-4-producing CD4 þ T cells was not different among patients with and without cGVHD and normal controls. These findings suggest that IL-4-producing CD8 þ T cells may be an immunological marker of cGVHD.

TCR Dependent Metabolic Programming Regulates Autocrine IL-4 Production Resulting in Self-Tuning of the CD8+ T Cell Activation Setpoint

“…Our finding that CD8 + T cells can discriminate the peptide/MHC level encountered during activation and respond by producing IL-4 that tunes their antigen sensitivity is a significant step forward in our understanding of the ability of CD8 + T cells to respond to environmental signals. The observation that CD8 + T cells can produce IL-4 is in agreement with other reports (25,(43)(44)(45); however this is, to our knowledge, the first demonstration of an antigen dependent mechanism through which this function is regulated. The ability of IL-4 to act as a regulator of CD8 + T cell function has been reported in models of exogenously added IL-4 (22-27, 34, 46-52).…”

“…The question arises as to why CD8 + T cells would possess this autocrine regulatory mechanism. IL-4 producing-CD8 + T cells elicited in vivo have been identified in chronic graft vs. host disease (45). These T cells tend to co-express IFNγ similar to what we observed in our studies.…”

Immunomodulatory effect of mesenchymal stem cells may depend on secretion of IL-2 and IL-10 and inhibition of TNF-α in pediatric hematopoietic stem cell donors and recipients

“…In breast cancer, an increased level of IL-4 was considered as a part of disease pathomechanism [21], while in stem cell transplantation setting IL-4 producing CD8+ lymphocytes seemed to contribute to development of chronic Graft-versusHost Disease [22]. In our observation, a significant increase in IL-4 in cultures only from recipients suggests the role of this cytokine in the underlying disease of those patients.…”

Effect of different conditioning regimens on survival and engraftment for children with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoeitic stem cell transplantation: A single institution experience

“…We combined treosulfan with fludarabine, thymoglobulin, and cyclophosphamide (60 mg/kg × 2 doses), resulting in a transplant preparative regimen that was lower in intensity than Conv MA regimens but stronger than the previous RIC regimen 9 . Pro‐inflammatory cytokines during HSCT have been associated with adverse outcomes 12‐14 . In animal studies, treosulfan has shown to cause lower levels of inflammatory cytokines compared to busulfan and cyclophosphamide, which may provide an additional advantage in particular in patients with HLH.…”