Murine cytomegalovirus promotes renal allograft inflammation via Th1/17 cells and IL-17A
AMERICAN JOURNAL OF TRANSPLANTATION(2022)
摘要
Human cytomegalovirus (HCMV) infection is associated with renal allograft failure. Allograft damage in animal models is accelerated by CMV-induced T helper 17 (Th17) cell infiltrates. However, the mechanisms whereby CMV promotes Th17 cell-mediated pathological organ inflammation are uncharacterized. Here we demonstrate that murine CMV (MCMV)-induced intragraft Th17 cells have a Th1/17 phenotype co-expressing IFN-gamma and/or TNF-alpha, but only a minority of these cells are MCMV specific. Instead, MCMV promotes intragraft expression of CCL20 and CXCL10, which are associated with recruitment of CCR6(+)CXCR3(+) Th17 cells. MCMV also enhances Th17 cell infiltrates after ischemia-reperfusion injury, independent of allogeneic responses. Pharmacologic inhibition of the Th17 cell signature cytokine, IL-17A, ameliorates MCMV-associated allograft damage without increasing intragraft viral loads or reducing MCMV-specific Th1 cell infiltrates. Clinically, HCMV DNAemia is associated with higher serum IL-17A among renal transplant patients with acute rejection, linking HCMV reactivation with Th17 cell cytokine expression. In summary, CMV promotes allograft damage via cytokine-mediated Th1/17 cell recruitment, which may be pharmacologically targeted to mitigate graft injury while preserving antiviral T cell immunity.
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关键词
basic (laboratory) research/science, clinical research/practice, kidney transplantation/nephrology, rejection: acute, cytokines/cytokine receptors, chemokines/chemokine receptors, infection and infectious agents-viral: cytomegalovirus (CMV)
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