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.