Abstract text
Introduction:
Induction of a robust immune response is essential for hosts to fight microbial infections. However, excessive immune responses without the presence of appropriate regulations also damage tissues, leading to immunopathology and death during infections. We have previously shown that IL-27 signaling is required for survival during African trypanosome infection by preventing lethal effect of CD4+ T cells and IFN-γ. However, the cellular and molecular mechanisms involved in preventing immunopathology still remain incompletely understood.
Objectivesto determine the cells and molecules involved in regulating immunopathology during T. brucei infection.
Materials & methods:Wild-type and knockout mice were infected with T. brucei. Flow cytometry, ELISA, and adoptive transfer experiments were performed to analyze the immune response in the infected mice.
ResultsWe found that CXCR6-/- mice infected with T. brucei survived significantly longer than infected wild-type mice, associated with demilished liver immunopathology and reduced pro-inflammatory cytokines including IFN-γ and TNF-α. Adoptive transfer of wild-type CD4+ T cells, but not CXCR6-/- CD4+ T cells, significantly reduced the survival of infected CXCR6-/- mice, demonstrating that CXCR6+CD4+ T cells mediated the early mortality of infected mice. Interestingly, mice deficient in LFA-1, an integrin molecule that is continuously expressed on Foxp3+ Tregs, died significantly earlier than wild-type mice during T. brucei infection, associated with enhanced activation of CD4+ T cells and higher secretion of IFN-γ. Importantly, infected LFA-1-/- mice exhibited significantly lower frequency and absolute number of Foxp3+ Tregs.
ConclusionCXCR6+CD4+ T cells promote early mortality of mice infected with T. brucei, while LFA-1 is essential for preventing the early mortality of infected mice, likely by maintaining Foxp3+ Tregs numerically and functionally.