Inhibition of innate co-receptor TREM-1 signaling reduces CD4(+) T cell activation and prolongs cardiac allograft survival.

ABSTRACT

The innate receptor "triggering-receptor-expressed-on-myeloid-cells-1" (TREM-1) enhances downstream signaling of "pattern recognition receptor" (PRR) molecules implicated in inflammatory responses. However the mechanistic role of TREM-1 in chronic heart rejection has yet to be elucidated. We examined the effect of TREM-1(+) antigen-presenting cells (APC) on alloreactive CD4(+) lymphocytes. Bm12 donor hearts were transplanted into wild-type MHC-class-II-mismatched C57BL/6J recipient mice. Progressive allograft rejection of bm12-donor hearts with decreased organ function, severe vasculopathy and allograft fibrosis was evident within 4 weeks. TREM-1(+) CD11b(+) MHC-II(+) F4/80(+) CCR2(+) APC and IFNγ-producing CD4(+) cells were detected during chronic rejection. Peptide inhibition of TREM-1 attenuated graft vasculopathy, reduced graft-infiltrating leukocytes and prolonged allograft survival, while being accompanied by sustained low levels of CD4(+) and CD8(+) cell infiltration. Remarkably, temporary inhibition of TREM-1 during early immune activation was sufficient for long-term allograft survival. Mechanistically, TREM-1 inhibition leads to reduced differentiation and proliferation of IFNγ-producing Th1 cells. In conclusion, TREM-1 influences chronic heart rejection by regulating the infiltration and differentiation of CD4(+) lymphocytes.