Abstract
BackgroundT helper (Th) 17 cells are a subset of T helper cells that express interleukin (IL)-17 and initiate the inflammatory response in autoimmune diseases. Regulatory T cells (Tregs) are a subpopulation of T cells that produce forkhead box P3 (FOXP3) and inhibit the immune response. Graft versus host disease (GVHD) is a complication of allogeneic tissue transplantation, and Th17 cells and their proinflammatory activity play a central role in the pathogenesis of GVHD. Gene associated with retinoid-interferon-induced mortality (GRIM) 19, originally identified as a nuclear protein, is expressed ubiquitously in various human tissues and regulate signal transducer and activator of transcription (STAT)3 activity.MethodsSplenoytes and bone marrow cells were transplanted into mice with GVHD. The alloresponse of T cells and GVHD clinical score was measured. Realtime-polymerase chain reaction (realtime-PCR) was used to examine mRNA level. Flow cytometry and enzyme linked immunosorbent assay (ELISA) was used to evaluate protein expression.ResultsA GRIM19 transgenic cell transplant inhibited Th17 cell differentiation, alloreactive T cell responses, and STAT3 expression in mice with GVHD. On the other hand, the differentiation of Tregs and STAT5 production were enhanced by GRIM19. Overall, the severity of GVHD was decreased in mice that had received GRIM19 transgenic bone marrow and spleen transplants. Transplantation from GRIM19-overexpressing cells downregulated the expression of nuclear factor of activated T cells (NFATc1) but promoted the expression of regulator of calcineurin (RCAN)3 while downregulating NFAT-dependent cytokine gene expression. This complex mechanism underlies the therapeutic effect of GRIM19.ConclusionsWe observed that GRIM19 can reduce Th17 cell differentiation and alloreactive T cell responses in vitro and in vivo. Additionally, GRIM19 suppressed the severity of GVHD by modulating STAT3 activity and controlling Th17 and Treg cell differentiation. These results suggest that GRIM19 attenuates acute GVHD through the inhibition of the excessive inflammatory response mediated by T cell activation.
Highlights
T helper (Th) 17 cells are a subset of T helper cells that express interleukin (IL)-17 and initiate the inflammatory response in autoimmune diseases
GRIM19 inhibits alloreactive T cell response both in vitro and in vivo As Graft versus host disease (GVHD) is induced by the activation of host-reactive donor T cells, persistence of alloreactive T cells is required for the development of GVHD [18]
In a mixed lymphocyte reaction (MLR), CD4+ T cells from B6 WT or GRIM19 Tg mice were cultured with allogeneic APCs
Summary
T helper (Th) 17 cells are a subset of T helper cells that express interleukin (IL)-17 and initiate the inflammatory response in autoimmune diseases. Graft versus host disease (GVHD) is a complication of allo‐ geneic tissue transplantation, and Th17 cells and their proinflammatory activity play a central role in the pathogenesis of GVHD. It has been demonstrated that GVHD is an immune inflammatory disease It is a complication of bone marrow transplants. When donor-derived T cells differentiate into T helper (Th) cell subsets, they can produce unique sets of transcription factors and cytokines that can damage host tissues [1,2,3]. Signal transducer and activator of transcription 3 (STAT3) has been described as an important regulator of Th17/Treg cells. Inhibition of STAT3 activation can reduce Th17 cell numbers but increase Treg numbers, attenuating inflammatory disorders [8, 9]
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