In Vivo CRISPR Screening Reveals CHD7 as a Positive Regulator of Short-lived Effector Cells.

CD8+ T cells differentiate into two subpopulations in response to acute viral infection: memory precursor effector cells (MPECs) and short-lived effector cells (SLECs). MPECs and SLECs are epigenetically distinct; however, the epigenetic regulators required for formation of these subpopulations are mostly unknown. In this study, we performed an in vivo CRISPR screen in murine naive CD8+ T cells to identify the epigenetic regulators required for MPEC and SLEC formation, using the acute lymphocytic choriomeningitis virus Armstrong infection model.

Epigenetic tuning of PD-1 expression improves exhausted T cell function and viral control.

PD-1 is a key negative regulator of CD8 T cell activation and is highly expressed by exhausted T cells in cancer and chronic viral infection. Although PD-1 blockade can improve viral and tumor control, physiological PD-1 expression prevents immunopathology and improves memory formation. The mechanisms driving high PD-1 expression in exhaustion are not well understood and could be critical to disentangling its beneficial and detrimental effects.

Central memory CD8+ T cells become CD69+ tissue-residents during viral skin infection independent of CD62L-mediated lymph node surveillance.

Memory CD8+ T cells in the circulation rapidly infiltrate non-lymphoid tissues following infection and provide protective immunity in an antigen-specific manner. However, the subsequent fate of memory CD8+ T cells after entering non-lymphoid tissues such as the skin during a secondary infection is largely unknown. Furthermore, because expression of CD62L is often used to identify the central memory (TCM) CD8+ T cell subset, uncoupling the physical requirement for CD62L-mediated lymph node homing versus other functional attributes of TCM CD8+ T cells remains unresolved.

Activation and trafficking of CD8 T cells during viral skin infection: immunological lessons learned from vaccinia virus.

Epicutaneous delivery of vaccinia virus (VacV) by scarification of the skin generates robust and durable protective immunity, which was ultimately responsible for eradicating smallpox from the human race. Therefore, infection of the skin with VacV is often used in experimental model systems to study the activation of adaptive immunity, as well as the development and functional features of immunological memory. Here, we describe recent advances using this viral infection to identify and characterize the mechanisms regulating the activation and trafficking of cytotoxic CD8 T cells into the inflamed skin, the migratory features of CD8 T cells within the skin microenvironment, and finally, their subsequent differentiation into tissue-resident memory cells.

Enzymatic synthesis of core 2 O-glycans governs the tissue-trafficking potential of memory CD8 T cells.

Trafficking of memory CD8 T cells out of the circulation is essential to provide protective immunity against intracellular pathogens in nonlymphoid tissues. However, the molecular mechanisms that dictate the trafficking potential of diverse memory CD8 T cell populations are not completely defined. We show that after infection or inflammatory challenge, central memory (T) CD8 T cells rapidly traffic into nonlymphoid tissues, whereas most effector memory cells remain in the circulation.

Local antigen in nonlymphoid tissue promotes resident memory CD8+ T cell formation during viral infection.

Tissue-resident memory (Trm) CD8(+) T cells are functionally distinct from their circulating counterparts and are potent mediators of host protection against reinfection. Whether local recognition of antigen in nonlymphoid tissues during infection can impact the formation of Trm populations remains unresolved. Using skin infections with vaccinia virus (VacV)-expressing model antigens, we found that local antigen recognition had a profound impact on Trm formation.