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.
Highlights
Multiple viruses infect the salivary gland and are shed into saliva for transmission to new hosts, including examples such as cytomegalovirus, Epstein Barr Virus, Human Herpesvirus 6, mumps virus, rabies virus, and even SARS-CoV-2 [1,2,3,4,5,6,7]
We found that murine cytomegalovirus (MCMV)-specific T cells in multiple tissues, including the salivary gland and kidney expressed PD-1, CD39 and CD73 at steady state, markers that are associated with recent antigen stimulation and T cell exhaustion
This expression of PD-1 was replicated throughout the body on tissue-localized MCMV-specific T cells
Summary
Multiple viruses infect the salivary gland and are shed into saliva for transmission to new hosts, including examples such as cytomegalovirus, Epstein Barr Virus, Human Herpesvirus 6, mumps virus, rabies virus, and even SARS-CoV-2 [1,2,3,4,5,6,7]. Many labs, including our own, have used the murine cytomegalovirus (MCMV) model to study viral infection of the salivary gland and the resulting T cell responses [8,9,10,11,12,13,14,15,16]. Primary infection typically occurs through contact with infected secretions (e.g. saliva, urine or breast milk), after which the virus spreads systemically in the body of the new host [17]. The immune system, and T cells in particular, must maintain continuous vigilance in order to control CMV for the life of the host
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