NK cell and Th17 responses are differentially induced in murine cytomegalovirus infected renal allografts and vary according to recipient virus dose and strain

Abstract

Human cytomegalovirus (HCMV) donor positive (D+) serostatus with acute rejection is associated with renal allograft loss, but the impact of recipient positive (R+) serostatus is unclear. In an allogeneic renal transplant model, antiviral natural killer (NK) and CD8+ T cell memory responses in murine CMV (MCMV) D+/R+ transplants were compared to D-/R- and D+/R- transplants, with recipient infection varied by MCMV dose and strain. D+/R- transplants had high primary antiviral cytolytic (interferon-γ+) and cytotoxic (granzyme B+) NK responses, whereas NK memory responses were lower in D+/R+ recipients receiving a high primary MCMV dose. Despite MCMV immunity, D+/R+ recipients receiving a low MCMV dose showed primary-like high cytolytic and cytotoxic NK responses. D+/R+ transplants infected with different D/R strains had low cytolytic NK responses but high cytotoxic NK responses. NK memory also induced a novel TNF-α+ NK response among high-dose virus recipients. MCMV+ transplants had greater Th17 responses than MCMV-uninfected transplants and Th17 inhibition ameliorated graft injury. All MCMV+ recipients had similar CD8+ T cell responses. In sum, NK and Th17 responses, but not CD8+ T cells, varied according to conditions of primary recipient infection. This variability could contribute to variable graft outcomes in HCMV D+/R+ renal transplantation.

Multiple infections by EBV, HCMV and Helicobacter pylori are highly frequent in patients with chronic gastritis and gastric cancer from Southwest Mexico

“…[58] In double and triple infections, H. pylori , EBV and HCMV can act synergistically, enhancing the expression of IL-17 and maintaining an inflammatory state that more severely damages gastric mucosa. [59–61] On the other hand, the oncoprotein CagA induces the secretion of IL-1β, IFN-ɣ, and TNF-α. IL-1β exerts its effects on gastric epithelial cells that might lead to the activation or expression of oncogenes.…”

“…[45,46,62,63] Dual infection increases IL-1β, TNF-α and IL-8 production, augments immune cell infiltration and there is more damage to gastric mucosa by the effect of the infection and of a more intense chronic inflammation. [16,45,59] It has been proposed that atrophic chronic gastritis and intestinal metaplasia caused by H. pylori augments gastric epithelium susceptibility to EBV infection and that in turn, viral infection promotes carcinogenesis. [58] Meanwhile, CagA induces PLCγ activation, which favors EBV reactivation on infected B cells in vitro [64] and both agents activate the β-catenin/TCF-4 pathway, which are transforming factors in gastric cells.…”

Th1/17 Cells Infiltrate Murine Cytomegalovirus-Infected Renal Allografts via Virus-Induced CCL20 and Promote Th1 Cells through IL-17A

“…In our prior studies, murine cytomegalovirus (MCMV) induced the infiltration of Th17 cells into murine renal allografts at day 14 post-transplantation 22 . To examine earlier events contributing to Th17 cell infiltration, allogeneic renal transplants were performed using donor (D) and recipient (R) MCMV negative (D-R-) and positive (D+R+) combinations with cyclosporine immunosuppression, sacrificed at day 7 post-transplant (Figure 1A), and frequencies of graft-infiltrating CD4 + T- cells expressing IL-17A, IFN-γ and TNF-α were quantified by intracellular cytokine staining/flow cytometry (ICS/FC) following PMA/ionomycin stimulation (Figures 1B and S1).…”

“…In rodent renal transplant models, rat CMV and MCMV infection exacerbate allograft inflammation and accelerate fibrosis 20, 21, 22 . Similar to clinical observations, valganciclovir prophylaxis in murine transplants inhibits viral reactivation and improves late allograft fibrosis 23, 24 .…”

“…Similar to clinical observations, valganciclovir prophylaxis in murine transplants inhibits viral reactivation and improves late allograft fibrosis 23, 24 . Recently, our group showed that T helper 17 (Th17) cells are induced in MCMV-infected allografts, and that IL-6 inhibition reduces Th17 cell infiltrates and histopathologic allograft injury 22 . Th17 cells produce IL-17A/F and other proinflammatory cytokines including IL-21, IL-22, and TNF-α, which contribute to inflammatory responses during autoimmune and infectious diseases and are also observed during allograft rejection 25, 26, 27, 28, 29 .…”