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

Tissue-resident memory CD8⁺ T cells (T_RMs) 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_RMs is unclear. Herein, we demonstrate that viral MHCI inhibition reduces the abundance of CD4⁺ and CD8⁺ T_RMs, 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_RMs.