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

Jossef F Osborn,Tahsin N Khan,Jake C Harbour,Jana L Mooster,Samuel J Hobbs,Augustus M Kilgore,Jeffrey C Nolz,Sumita Bhaduri-Mcintosh

doi:10.1371/journal.ppat.1007633

Abstract

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. Here, we show that in contrast to naïve CD8+ T cells, memory CD8+ T cells traffic into the skin independent of CD62L-mediated lymph node re-activation and provide robust protective immunity against Vaccinia virus (VacV) infection. TCM, but not effector memory (TEM), CD8+ T cells differentiated into functional CD69+/CD103- tissue residents following viral clearance, which was also dependent on local recognition of antigen in the skin microenvironment. Finally, we found that memory CD8+ T cells expressed granzyme B after trafficking into the skin and utilized cytolysis to provide protective immunity against VacV infection. Collectively, these findings demonstrate that TCM CD8+ T cells become cytolytic following rapid infiltration of the skin to protect against viral infection and subsequently differentiate into functional CD69+ tissue-residents.

Highlights

Following acute infection or successful vaccination, antigen-specific CD8+ T cells that survive contraction differentiate into long-lived memory cells that provide protective immunity against re-infection
the central memory (TCM), but not TEM, trafficked into the skin and differentiated into functional tissue-resident”memory cells (TRM) following resolution of viral infection and this occurred independent of the ability of these cells to home into and survey peripheral lymph nodes
Our findings demonstrate that a defined lineage of circulating memory CD8+ T cells are the principle responders against viral skin infection and the precursors to secondary TRM CD8+ T cells that form, which are important considerations for understanding host defense mechanisms against recurring viral infections and tissue-specific vaccine development

Summary

Introduction

Following acute infection or successful vaccination, antigen-specific CD8+ T cells that survive contraction differentiate into long-lived memory cells that provide protective immunity against re-infection. Memory CD8+ T cells exhibit a variety of functional characteristics (e.g. production of cytokines, cytolytic activity) that allow them to provide protective immunity against viruses and other intracellular pathogens [1, 2]. Understanding the mechanisms that control both the formation and protective features of these diverse memory T cell populations remains a challenge for rational vaccine design and development. Both TRM and memory CD8+ T cells in the circulation provide protective immunity against re-infections of the skin and other non-lymphoid tissues. In response to inflammatory cues, circulating memory CD8+ T cells rapidly enter non-lymphoid tissues and provide significant protective immunity against viral skin infection [14, 15]. The protective mechanisms used by circulating memory CD8+ T cells to control viral infection after trafficking into the skin are largely undefined

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