TY - JOUR
T1 - Murine cytomegalovirus promotes renal allograft inflammation via Th1/17 cells and IL-17A
AU - Dhital, Ravi
AU - Anand, Shashi
AU - Graber, Brianna
AU - Zeng, Qiang
AU - Velazquez, Victoria M.
AU - Boddeda, Srinivasa R.
AU - Fitch, James R.
AU - Minz, Ranjana W.
AU - Minz, Mukut
AU - Sharma, Ashish
AU - Cianciolo, Rachel
AU - Shimamura, Masako
N1 - Publisher Copyright:
© 2022 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.
PY - 2022/10
Y1 - 2022/10
N2 - 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-γ and/or TNF-α, 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.
AB - 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-γ and/or TNF-α, 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.
KW - basic (laboratory) research/science
KW - chemokines/chemokine receptors
KW - clinical research/practice
KW - infection and infectious agents—viral: cytomegalovirus (CMV)
KW - kidney transplantation/nephrology
KW - rejection: acute, cytokines/cytokine receptors
UR - http://www.scopus.com/inward/record.url?scp=85131840628&partnerID=8YFLogxK
U2 - 10.1111/ajt.17116
DO - 10.1111/ajt.17116
M3 - Article
C2 - 35671112
AN - SCOPUS:85131840628
SN - 1600-6135
VL - 22
SP - 2306
EP - 2322
JO - American Journal of Transplantation
JF - American Journal of Transplantation
IS - 10
ER -