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

Date Published: March 15, 2019

Publisher: Public Library of Science

Author(s): Jossef F. Osborn, Samuel J. Hobbs, Jana L. Mooster, Tahsin N. Khan, Augustus M. Kilgore, Jake C. Harbour, Jeffrey C. Nolz, Sumita Bhaduri-McIntosh.


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.

Partial Text

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]. Another key feature of memory CD8+ T cells is their acquired ability to infiltrate and/or be retained in non-lymphoid tissues, whereas naïve CD8+ T cells are largely restricted to the circulation and secondary lymphoid organs [3, 4]. Memory CD8+ T cells can be broadly classified as those that are present in the circulation and those that remain in non-lymphoid tissues, now referred to as “tissue-resident” memory cells (TRM) [5]. Because of their location, often at environmental barriers, it is believed that pro-inflammatory TRM CD8+ T cells are the cells most responsible for immediate protection against re-infections [6–10], prior to the trafficking of additional circulating memory CD8+ T cells into the site of infection to further promote pathogen clearance [11]. 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.

TRM CD8+ T cells are believed to play an important role in host defense against pathogens, but have also been suggested to be the dysfunctional culprit in a variety of inflammatory diseases of the skin and perhaps other non-lymphoid tissues [36, 37]. Thus, an understanding of both the cell intrinsic mechanisms, as well as the cell extrinsic microenvironment inflammatory factors that ultimately control the formation of these cell populations is highly relevant for a variety of diseases and pathological conditions. Most studies to date have focused on the capacity for TRM CD8+ T cells to develop from naïve CD8+ T cells following a primary infection in mice, where no protective adaptive immunity against the pathogen is present. Notably, there are essentially no TRM CD8+ T cells in laboratory mice prior to any type of experimental manipulation, whereas human skin is rich in a heterogeneous mixture of CD8+ and CD4+ T cells exhibiting a variety of phenotypes [22]. This observation suggests that exposure to environmental antigens and pathogens throughout life is continually shaping the composition of the skin T cell repertoire [38]. Because most of our current knowledge of the mechanisms controlling TRM formation have been studied in the context of a primary infection, understanding how pre-existing immunological memory and dynamic host-pathogen interactions within the local tissue microenvironment impact TRM differentiation has remained largely unknown.




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