Regulation of Pulmonary Graft-versus-Host Disease by IL-26+CD26+CD4 T Lymphocytes

Abstract

Obliterative bronchiolitis is a potentially life-threatening noninfectious pulmonary complication after allogeneic hematopoietic stem cell transplantation and the only pathognomonic manifestation of pulmonary chronic graft-versus-host disease (cGVHD). In the current study, we identified a novel effect of IL-26 on transplant-related obliterative bronchiolitis. Sublethally irradiated NOD/Shi-scidIL2rγnull mice transplanted with human umbilical cord blood (HuCB mice) gradually developed clinical signs of graft-versus-host disease (GVHD) such as loss of weight, ruffled fur, and alopecia. Histologically, lung of HuCB mice exhibited obliterative bronchiolitis with increased collagen deposition and predominant infiltration with human IL-26+CD26+CD4 T cells. Concomitantly, skin manifested fat loss and sclerosis of the reticular dermis in the presence of apoptosis of the basilar keratinocytes, whereas the liver exhibited portal fibrosis and cholestasis. Moreover, although IL-26 is absent from rodents, we showed that IL-26 increased collagen synthesis in fibroblasts and promoted lung fibrosis in a murine GVHD model using IL-26 transgenic mice. In vitro analysis demonstrated a significant increase in IL-26 production by HuCB CD4 T cells following CD26 costimulation, whereas Ig Fc domain fused with the N-terminal of caveolin-1 (Cav-Ig), the ligand for CD26, effectively inhibited production of IL-26. Administration of Cav-Ig before or after onset of GVHD impeded the development of clinical and histologic features of GVHD without interrupting engraftment of donor-derived human cells, with preservation of the graft-versus-leukemia effect. These results therefore provide proof of principle that cGVHD of the lungs is caused in part by IL-26+CD26+CD4 T cells, and that treatment with Cav-Ig could be beneficial for cGVHD prevention and therapy.

Combined OX40L and mTOR blockade controls effector T cell activation while preserving T reg reconstitution after transplant

“…Analysis of the resulting dataset using DAVID (26, 27) revealed statistically significant enrichment for two pathways: the KEGG hsa04630: Jak-STAT signaling pathway and the Reactome HSA-909733: Interferon α/β signaling pathway. Enrichment in the Jak-STAT pathway was identified with both DAVID-based pathway analysis and GSEA (Figure 7C, top panel , and Table S1) and revealed a complex enrichment pattern, that included transcripts encoding both pro- and anti-inflammatory cytokines/cytokine receptors (pro-inflammatory transcripts included IL6, IL6R and IL6ST (28); IL26 (29); anti-inflammatory transcripts included OSM (30), IL2RA and IL-10RB (31), CSF3R (32), and IL13RA1 (33)). In addition, both positive and negative regulators of Jak-STAT and TCR signaling cascades were enriched (positive regulators included STAT1, STAT2 and STAT3; negative regulators included SOCS1 and, SOCS2, PIM1, SOS1 and SOS2, CISH, PIAS1, SPRY1 (34-36)).…”

Identification of human CD4+T cell populations with distinct antitumor activity

“…CD26 expressing cells further have high levels of chemokine receptors on their cell surface including CCR2 which promote their recruitment and migration capability and are associated with rapid functional recall responses ( 1, 20 ). CD26 + T cells have been associated with exacerbating various autoimmune manifestations, including rheumatoid arthritis (RA) ( 21 ), multiple sclerosis (MS) ( 22 ), graft versus host disease (GVHD) ( 23, 24 ) and diabetes ( 25 ). Conversely, levels of CD26 enzymatic activity and the number of CD26 + T cells decrease in the blood of melanoma patients as their disease progresses ( 26 ).…”

Unravelling the immunological roles of dipeptidyl peptidase 4 (DPP4) activity and/or structure homologue (DASH) proteins

“…DPP4/ CD26 is involved in T cell activation, T cell signalling and T cell differentiation due to its interactions with ADA, CD45, caveolin-1, CARMA-1 and M6P/IGFII-R [9]. These processes are regulated by the cytokines IL-2, IL-6, IL-10, IL-12, IL-17, IL-29, IFN-g and TGF-b, as well as compartmentation of DPP4/CD26 to either lipid rafts or internalization [8,9,48,88,89,[91][92][93]. Furthermore, post-translation modification of DPP4/CD26 such as sialylation also appears to influence compartmentation and/or the interactions with its binding partners [9,86,87,90].…”

“…In addition, DPP4/CD26 is expressed highly on the CD45RO 1 CD29 1 memory T helper subset CD26 bright CD4 1 , which responds to recall antigens, induces B cell immunoglobulin (Ig)G synthesis and activates cytotoxic T cells [7,8,13,51,94,96]. CD26/DPP4 also plays a role in chronic pulmonary graft-versus-host disease with up-regulation of IL-26, involving CD26 and caveolin-1 interactions [91]. Furthermore, DPP4 is up-regulated in activated natural killer (NK) cells, B cells, eosinophils and macrophages [9,13,44,45,51,94].…”