Purpose of review

This review summarizes recent literature defining tissue-resident memory T cells (T_RM) and discusses implications for HIV pathogenesis, vaccines, and eradication efforts.

Recent findings

Investigations using animal models and human tissues have identified a T_RM transcriptional profile and elucidated signals within the tissue microenvironment leading to T_RM development and maintenance. T_RM are major contributors to host response in infectious diseases and cancer; in addition, T_RM contribute to pathogenic inflammation in a variety of settings. Although T_RM are daunting to study in HIV infection, recent work has helped define their molecular signatures and effector functions and tested strategies for their mobilization. Exclusive reliance on blood sampling to gain an understanding of host immunity overlooks the contribution of T_RM, which differ in significant ways from their counterparts in circulation. It is hoped that greater understanding of these cells will lead to novel approaches to prevent and/or eradicate HIV infection.

Purpose of review

This review summarizes our current understanding of HIV-1-specific T-cell responses in mucosal tissues, emphasizing recent work and specifically highlighting papers published over the past 18 months.

Recent findings

Recent work has improved the standardization of tissue sampling approaches and provided new insights on the abundance, phenotype and distribution of HIV-1-specific T-cell populations in mucosal tissues. In addition, it has recently been established that some lymphocytes exist in tissues as "permanent resident" memory cells that differ from their counterparts in blood.

Summary

HIV-1-specific T-cell responses have been extensively characterized; however, the vast majority of reports have focused on T-cells isolated from peripheral blood. Mucosal tissues of the genitourinary and gastrointestinal tracts serve as the primary sites of HIV-1 transmission, and provide "front line" barrier defenses against HIV-1 and other pathogens. In addition, the gastrointestinal tract remains a significant viral reservoir throughout the chronic phase of infection. Tissue-based immune responses may be critical in fighting infection, and understanding these defenses may lead to improved vaccines and immunotherapeutic strategies.

The gastrointestinal mucosa is an important site of HIV acquisition, viral replication, and pathogenesis. Immune cells in mucosal tissues frequently differ in phenotype and function from their non-mucosal counterparts. Although perforin-mediated cytotoxicity as measured in blood is a recognized correlate of HIV immune control, its role in gastrointestinal tissues is unknown. We sought to elucidate the cytotoxic features of rectal mucosal CD8⁺ T-cells in HIV infected and uninfected subjects. Perforin expression and lytic capacity were significantly reduced in rectal CD8⁺ T-cells compared with their blood counterparts, regardless of HIV clinical status; granzyme B (GrzB) was reduced to a lesser extent. Mucosal perforin and GrzB expression were higher in participants not on antiretroviral therapy compared with those on therapy and controls. Reduction in perforin and GrzB was not explained by differences in memory/effector subsets. Expression of T-bet and Eomesodermin was significantly lower in gut CD8⁺ T-cells compared with blood, and in vitro neutralization of TGF-β partially restored perforin expression in gut CD8⁺ T-cells. These findings suggest that rectal CD8⁺ T-cells are primarily non-cytotoxic, and phenotypically shaped by the tissue microenvironment. Further elucidation of rectal immune responses to HIV will inform the development of vaccines and immunotherapies targeted to mucosal tissues.

We previously reported that CD8⁺ T cells in human gastrointestinal mucosa exhibit reduced perforin expression and weak or impaired cytotoxic capacity compared with their counterparts in blood. Nevertheless, these cells degranulate and express cytokines and chemokines in response to cognate Ag. In addition to weak expression of perforin, earlier studies suggested differential regulation of perforin and granzymes (Gzms), with GzmA and B expressed by significantly higher percentages of mucosal CD8⁺ T cells than perforin. However, this topic has not been fully explored. The goal of this study was to elucidate the expression and coexpression patterns of GzmA, B, and K in conjunction with perforin in rectosigmoid CD8⁺ T cells during HIV-1 infection. We found that expression of both perforin and GzmB, but not GzmA or GzmK, was reduced in mucosa compared with blood. A large fraction of rectosigmoid CD8⁺ T cells either did not express Gzms or were single-positive for GzmA. Rectosigmoid CD8⁺ T cells appeared skewed toward cytokine production rather than cytotoxic responses, with cells expressing multiple cytokines and chemokines generally lacking in perforin and Gzm expression. These data support the interpretation that perforin and Gzms are differentially regulated, and display distinct expression patterns in blood and rectosigmoid T cells. These studies may help inform the development of strategies to combat HIV-1 and other mucosal pathogens.

Tissue-resident memory (T_RM) CD8⁺ T-cells are non-recirculating, long-lived cells housed in tissues that can confer protection against mucosal pathogens. Human immunodeficiency virus-1 (HIV-1) is a mucosal pathogen and the gastrointestinal tract is an important site of viral pathogenesis and transmission. Thus, CD8⁺ T_RM cells may be an important effector subset for controlling HIV-1 in mucosal tissues. This study sought to determine the abundance, phenotype, and functionality of CD8⁺ T_RM cells in the context of chronic HIV-1 infection. We found that the majority of rectosigmoid CD8⁺ T-cells were CD69⁺CD103⁺S1PR1^- and T-bet^LowEomesodermin^Neg, indicative of a tissue-residency phenotype similar to that described in murine models. HIV-1-specific CD8⁺ T_RM responses appeared strongest in individuals naturally controlling HIV-1 infection. Two CD8⁺ T_RM subsets, distinguished by CD103 expression intensity, were identified. CD103^Low CD8⁺ T_RM primarily displayed a transitional memory phenotype and contained HIV-1-specific cells and cells expressing high levels of Eomesodermin, whereas CD103^High CD8⁺ T_RM primarily displayed an effector memory phenotype and were Eomesodermin^Neg. These findings suggest a large fraction of CD8⁺ T-cells housed in the human rectosigmoid mucosa are tissue-resident and that T_RM contribute to the anti-HIV-1 immune response. Further exploration of CD8⁺ T_RM will inform development of anti-HIV-1 immune-based therapies and vaccines targeted to the mucosa.