Retinoic acid–responsive CD8 effector T cells are selectively increased in IL-23–rich tissue in gastrointestinal GVHD

Abstract

Gastrointestinal (GI) graft-versus-host disease (GvHD) is a major barrier in allogeneic hematopoietic stem-cell transplantation (AHST). The metabolite retinoic acid (RA) potentiates GI-GvHD in mice via alloreactive T-cells expressing the RA-receptor-alpha (RARα), but the role of RA-responsive cells in human GI-GvHD remains undefined. We therefore used conventional and novel sequential immunostaining and flow cytometry to scrutinize RA-responsive T-cells in tissues and blood of AHST patients and characterize the impact of RA on human T-cell alloresponses. Expression of RARα by human mononuclear cells was increased after RA exposure. RARαhi mononuclear cells were increased in GI-GvHD tissue, contained more cellular RA-binding proteins, localized with tissue damage and correlated with GvHD severity and mortality. Using a targeted candidate protein approach we predicted the phenotype of RA-responsive T-cells in the context of increased microenvironmental IL-23. Sequential immunostaining confirmed the presence of a population of RARahi CD8 T-cells with the predicted phenotype, co-expressing the effector T-cell transcription factor T-bet and the IL-23-specific receptor. These cells were increased in GI- but not skin-GvHD tissues and were also selectively expanded in GI-GvHD patient blood. Finally, functional approaches demonstrated RA predominantly increased alloreactive GI-tropic RARahi CD8 effector T-cells, including cells with the phenotype identified in vivo. IL-23-rich conditions potentiated this effect by selectively increasing b7 integrin expression on CD8 effector T-cells and reducing CD4 T-cells with a regulatory cell phenotype. In conclusion we have identified a population of RA-responsive effector T-cells with a distinctive phenotype which are selectively expanded in human GI-GvHD and represent a potential new therapeutic target.

Bioinformatics analysis identified immune infiltration, risk and drug prediction models of copper-induced death genes involved in salivary glands damage of primary Sjögren’s syndrome

“…[ 45 , 46 ] ATRA down-regulated IL-6Rα and IL-23R and played an important role in differentiation of Th17. [ 47 , 48 ]…”

“…[45,46] ATRA down-regulated IL-6Rα and IL-23R and played an important role in differentiation of Th17. [47,48] Resveratrol (Res) is a natural non-flavonoid polyphenol compound, which has strong immunomodulatory and anti-inflammatory effects. [49] Res increased IL-10 and deacetylase 1, and effectively improved the salivation dysfunction in non-obese diabetic mice.…”

Interleukin 23 receptor: Expression and regulation in immune cells

“…IL23R + IL‐17A + CD8 + αβ T cells are enriched in synovial fluid from psoriatic arthritis patients, suggesting that these cells may support chronic inflammation [63]. Similarly to what was observed for Th1 cells, enrichment of T‐bet + IL‐23R + CD8 + T cells was observed in the intestine and blood of Graft‐versus‐Host Disease patients [64].…”

EULAR study group on ‘MHC-I-opathy': identifying disease-overarching mechanisms across disciplines and borders

“… 148 151 Here, the cytokine IL-23 eliminates thymic regulatory T cells in an IL23R-dependent manner, 152 while selectively enriching IL23R-expressing CD8+T cells. 153 Moreover, there is no sharp affinity threshold for the recognition of MHC-peptide complex by TCRs, and CD8+T cells with otherwise low affinity TCRs can be activated by a large increase in presented autoantigen. 154 155 This also fits with the recently proposed ‘autoimmune surveillance of hypersecreting mutants’ theory that links high autoantigen levels to T-cell autoimmunity.…”