Viral MHCI inhibition evades tissue-resident memory T cell formation and responses

Tissue-resident memory CD8(+) T cells (T(RM)s) confer rapid protection and immunity against viral infections. Many viruses have evolved mechanisms to inhibit MHCI presentation in order to evade CD8(+) T cells, suggesting that these mechanisms may also apply to T(RM)-mediated protection. However, the effects of viral MHCI inhibition on the function and generation of T(RM)s is unclear. Herein, we demonstrate that viral MHCI inhibition reduces the abundance of CD4(+) and CD8(+) T(RM)s, but its effects on the local microenvironment compensate to promote antigen-specific CD8(+) T(RM) formation. Unexpectedly, local cognate antigen enhances CD8(+) T(RM) development even in the context of viral MHCI inhibition and CD8(+) T cell evasion, strongly suggesting a role for in situ cross-presentation in local antigen-driven T(RM) differentiation. However, local cognate antigen is not required for CD8(+) T(RM) maintenance. We also show that viral MHCI inhibition efficiently evades CD8(+) T(RM) effector functions. These findings indicate that viral evasion of MHCI antigen presentation has consequences on the development and response of antiviral T(RM)s.