Lung parenchyma-derived IL-6 promotes IL-17A–dependent acute lung injury after allogeneic stem cell transplantation

Abstract

Key Points IL-6 is dysregulated after experimental allogeneic SCT and promotes alloantigen-dependent Th17 expansion within the lung. IL-6 is dysregulated in patients with IPS after clinical allogeneic SCT.

Th17 plasticity and transition toward a pathogenic cytokine signature are regulated by cyclosporine after allogeneic SCT

“…Using an allo-SCT-induced model of lung injury, we have previously demonstrated the importance of IL-6 in driving Th17 development. 2 Here, we also observed Th17 differentiation to be highly dependent upon IL-6R signaling in all tissues examined ( Figure 1C). IL-17A expression was transient such that the proportion of CD4…”

“…Although calcineurin inhibition is known to have broad immunosuppressive effects on T-cell responses, including a significant reduction in overall Th17 frequencies, 2 we found that CsA treatment successfully reduced the transition of IL-17A 1 IFNg -Th17 toward an IFNg2producing phenotype ( Figure 4A-B). Because we have previously demonstrated that donor antigen-presenting cells (APCs) are a major source of IL-12 posttransplant, 37 we examined the effect of CsA using IL-12p40-YFP reporter mice.…”

“…2,36 Therefore, we assessed the influence of CsA treatment on Th17 cytokine plasticity by exposing mice to increasing doses of CsA …”

“…This effect is perhaps most prominent in interleukin-17 (IL-17)-producing donor T cells, which we and others have shown to be highly pathogenic in preclinical models of GVHD. [1][2][3][4][5][6] Plasticity has been widely reported in CD4 IL-17A 1 (Tc17) T cells in a range of infectious and autoimmune settings. [6][7][8][9][10][11][12] We have recently described Tc17 cytokine plasticity in murine allo-SCT recipients, 1 which is characteristic of a hyper-proinflammatory T-cell subset that contributes to GVHD but fails to mediate graft-versus-leukemia effects.…”

Cytokines in Graft-versus-Host Disease

“…Cutaneous pathology also may be generated by Th17 cells; although they are more commonly associated with chronic GVHD (cGVHD), they also have been associated with acute pathology (22)(23)(24). Th17 differentiation is initiated by IL-6 (25), and RORgt is the defining transcription factor (26), whereas maintenance and amplification relies on IL-23 and IL-21, respectively (27).…”