Inhibitory Molecules PD-1, CD73 and CD39 Are Expressed by CD8+ T Cells in a Tissue-Dependent Manner and Can Inhibit T Cell Responses to Stimulation
Corinne J. Smith, Christopher M. Snyder
Abstract
The salivary gland is an important tissue for persistence and transmission of multiple viruses. Previous work showed that salivary gland tissue-resident CD8 + T cells elicited by viruses were poorly functional ex vivo . Using a model of persistent murine cytomegalovirus (MCMV) infection, we now show that CD8 + T cells in the salivary gland and other non-lymphoid tissues of mice express multiple molecules associated with T cell exhaustion including PD-1, CD73 and CD39. Strikingly however, these molecules were expressed independently of virus or antigen. Rather, PD-1-expressing T cells remained PD-1 + after migration into tissues regardless of infection, while CD73 was activated on CD8 + T cells by TGF-β signaling. Blockade of PD-L1, but not CD73, improved cytokine production by salivary gland T cells ex vivo and increased the expression of granzyme B after stimulation within the salivary gland. Nevertheless, salivary-gland localized CD8 + T cells could kill PD-L1-expressing targets in vivo , albeit with modest efficiency, and this was not improved by PD-L1 blockade. Moreover, the impact of PD-L1 blockade on granzyme B expression waned with time. In contrast, the function of kidney-localized T cells was improved by CD73 blockade, but was unaffected by PD-L1 blockade. These data show that tissue localization per se is associated with expression of inhibitory molecules that can impact T cell function, but that the functional impact of this expression is context- and tissue-dependent.