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

Abstract

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.

Figure 1. Biphasic CD8⁺ T cell activation occurs in the draining lymph node following VacV infection

Early during infection (< ~30 hours), virus drains directly into the lymph node and infects macrophages and dendritic cells (DCs). This provokes a spatial reorganization of naïve CD8⁺ T cells as they migrate to the peripheral interfollicular region (PIR), coordinated in part by CCR5. Later during infection (> ~48 hours), cross presentation dominates T cell activation and cross-presenting DCs (such as the XCR1+ subset) form contacts with naïve CD8⁺ T cells in the paracortex region of the draining lymph node. In both cases, activated T cells subsequently exit the lymph node via the efferent lymph.

Figure 2. Trafficking and migration of CD8⁺ T cells into VacV-infected skin

Following their activation in the draining lymph node (see Figure 1), effector CD8⁺ T cells enter the circulation and passively transit in the blood stream until they encounter activated vascular endothelium. Activated vascular endothelium expresses adhesion molecules (e.g. E- and P-selectin) and chemokines that are necessary for recruiting circulating CD8⁺ T cells out of the circulation and into VacV-infected skin. Recently activated effector CD8⁺ T cells (or previously activated memory CD8⁺ T cells) infiltrate the skin microenvironment, where chemotactic cues such as the CXCR3 ligands CXCL9 and CXCL10 direct their migration toward VacV-infected keratinocyte foci. When CD8⁺ T cells in the skin encounter antigen, this causes them to subsequently differentiate into tissue-resident memory CD8⁺ T cells that are maintained for extended periods of time in the skin and are potent mediators of protection against re-infection.