Functional responses of salivary gland resident T cells are suppressed by extracellular adenosine

Abstract

Tissue-resident memory T cells (TRM) survive and persist within non-lymphoid tissues throughout the body, and are therefore subjected to an array of tissue-specific environments. Previous work showed that T cells extracted from the salivary gland were markedly dysfunctional for cytokine secretion upon ex vivo stimulation. This finding is important since the salivary gland is a site of shedding for several viruses. Cytomegalovirus (CMV) is a herpesvirus that persists in the salivary gland and is shed in saliva. Using the natural mouse pathogen murine (M)CMV, we previously showed that most MCMV-specific T cells in the salivary gland readily become TRM. Interestingly, CD8+ TRM in the salivary gland, but not T cells in the spleen, expressed both CD39 and CD73 ectoenzymes that break down extracellular adenosine triphosphate (ATP) to the immunosuppressive molecule adenosine. Expression of CD73 was dependent on TGF-β and neither CD39 nor CD73 expression was dependent on MCMV infection. Importantly, blocking the adenosine receptor A2AR during stimulation restored the function of CD8+TRM recovered from the salivary gland, resulting in IFN-γ and TNF-α production by salivary gland TRM that was comparable to T cells from the spleen. These data suggest that extracellular adenosine inhibits the function of salivary gland CD8+ TRM and that any ATP released during infection may be converted to adenosine by the TRM cells themselves, an avenue we are currently pursuing by use of mass spectrometry with and without MCMV infection.