Memory T Cell Subsets, Migration Patterns, and Tissue Residence

Abstract

Tissues such as the skin and mucosae are frequently exposed to microbial pathogens. Infectious agents must be quickly and efficiently controlled by our immune system, but the low frequency of naive T cells specific for any one pathogen means dependence on primary responses initiated in draining lymph nodes, often allowing time for serious infection to develop. These responses imprint effectors with the capacity to home to infected tissues; this process, combined with inflammatory signals, ensures the effective targeting of primary immunity. Upon vaccination or previous pathogen exposure, increased pathogen-specific T cell numbers together with altered migratory patterns of memory T cells can greatly improve immune efficacy, ensuring infections are prevented or at least remain subclinical. Until recently, memory T cell populations were considered to comprise central memory T cells (TCM), which are restricted to the secondary lymphoid tissues and blood, and effector memory T cells (TEM), which broadly migrate between peripheral tissues, the blood, and the spleen. Here we review evidence for these two memory populations, highlight a relatively new player, the tissue-resident memory T cell (TRM), and emphasize the potential differences between the migratory patterns of CD4(+) and CD8(+) T cells. This new understanding raises important considerations for vaccine design and for the measurement of immune parameters critical to the control of infectious disease, autoimmunity, and cancer.

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 + T EM and CD8 + T RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

“…Thus, based on these new findings, a worthy goal of a herpes immunotherapeutic vaccine should be to develop a vaccine strategy that would generate and maintain a sufficient number of antiviral memory CD8 ϩ T EM and CD8 ϩ T RM cells within peripheral tissues, such as latently infected TG, the root of virus reactivation that leads to virus shedding and recurrent ocular herpetic disease (23)(24)(25)(26). However, this goal remains unattainable because the TG appear to be a "closed immunological compartment" to accepting homing of conventional circulating memory CD8 ϩ T cell subpopulations such as the CD8 ϩ T EM cells that could be migrating into latently infected TG from the neighboring draining lymph nodes through the circulation system (14,43). To overcome this challenge, our study demonstrates for the first time that changing the microenvironment of latently infected TG in CXCL10 Ϫ/Ϫ deficient mice by increasing the amount of local CXCL10 chemokine had the following effects: (i) rescued the number of both CD8 ϩ T EM and CD8 ϩ T RM cell subpopulations in TG, (ii) reversed the exhaustion of CD8 ϩ T EM and CD8 ϩ T RM cells in TG, and (iii) reduced recurrent corneal herpetic disease.…”

“…It is likely that accumulation of a sufficient number of CD8 ϩ T EM and CD8 ϩ T RM cells within latently infected TG, by a yet-to-be determined CXCL10/CXCR3-dependent mechanism, reduced virus reactivation from latency. Since the TG appear to be an immunological compartment that is closed during latency to accepting homing of circulating CD8 ϩ T CM and CD8 ϩ T EM cells, which could be coming from the draining lymph nodes through the circulation system (14,43), it is very likely that T RM cells are the main T cell subpopulation that contribute to suppressing (or aborting) attempts of HSV-1 reactivation from latently infected neurons.…”

The roles of resident, central and effector memory CD4 T‐cells in protective immunity following infection or vaccination

“…This enables them to tailor the immune response depending on the type of pathogen, and to perform multiple functions at different sites during a single infection. Memory CD4 T‐cells retain characteristics of the activated CD4 T‐cells from which they are derived and can, therefore, also be divided based on their functional responses 4, 5. This cellular memory is thought to be retained by epigenetic changes to the cell's DNA or associated histone proteins that keep genes in an open or closed state depending on their expression during the primary immune response 3, 6, 7.…”

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

“…The concept of tissue-resident memory CD8 + T-cells is now established for several types of tissues and infections [84][85][86][87] . Indeed, PD-1 positive CD8 + T-cells have been found to be preferentially retained in bone marrow, lymph nodes, kidney, and brain after chronic LCMV clone-13 infection 42 .…”