Emerging concepts in tissue-resident T cells: lessons from humans

Abstract

Intensified efforts to promote protective T cell-based immunity in vaccines and immunotherapies have created a compelling need to expand our understanding of human T cell function and maintenance beyond its characterization in peripheral blood. Mouse studies of T cell immunity show that, in response to infection, T cells migrate to diverse sites and persist as tissue-resident memory T cells (TRM), which mediate rapid in situ protection on antigen recall. Here we discuss new approaches to probe human T cell immunity, including novel sampling, that indicate a broad distribution and high frequency of human TRM in multiple sites. These newer findings further implicate anatomic compartmentalization as a generalized mechanism for long-term maintenance of human T cells throughout life.

Keywords: immune homeostasis; immune memory; mucosal immunity; naïve T cells; peripheral blood.

Figure 1. Variegation of TRM phenotypes in different tissue sites

Expression of the TRM markers CD69 and CD103 on CD4⁺ and CD8⁺ TEM populations in tissue sites (indicated on horizontal axis) is depicted by proportion CD69⁺ based on position on the vertical axis, and proportion CD103⁺, indicated by colored shading of each cell type (ranging from yellow=0% to deep red/brown=100%). CD69 is absent on circulating cells and is progressively upregulated on TEM with the highest expression levels seen in mucosal sites. CD103 expression is highest in CD8⁺ TEM in mucosal tissue sites and mucosal-draining LN with variable expression by CD8⁺TEM in other tissues, and CD4⁺ TEM exhibit low or negligible CD103 expression.

Figure 2. Differentiation and homeostasis of circulating and tissue T cell subsets

Proposed differentiation patterns of CD8⁺ and CD4⁺ T cells from naïve (red) to the generation of TRM (white), TEM (black) and TEMRA (green), indicating the tissue-specific maintenance and migration of each subset. (A) Activation of naïve CD8⁺ T cells may generate TEMRA in blood, or TEM which can migrate to mucosal and other peripheral tissues (e.g., skin). TRM can either be generated from the activated/effector cells which migrate to tissue sites following infection, or could go through a TEM intermediate via further activation or homeostatic turnover. (B) Activation of naïve CD4⁺T cells can generate TCM as a potential intermediate state migrating to blood and lymphoid tissue, prior to the generation of TEM which migrates to multiple sites. CD4⁺ TRM could develop from activated/effector CD4⁺ T cells or CD4⁺ TEM as in (A). All subsets with access to circulation undergo increased homeostatic proliferation in peripheral blood compared to tissues (see dotted arrows). TEMRA in CD8⁺ T cells and TCM in CD4⁺ T cells comprise a circulating subset limited to sites with access to peripheral blood whereas TRM are relegated to tissue sites and are protected from circulation.

Figure 3. Naïve T cell compartmentalization and migration in lymphoid tissues

Diagram showing potential compartmentalization of naïve T cells in different lymph nodes (LN1 and LN2) following export from the thymus. Recent thymic emigrants (RTE, red) emerge from the thymus through circulation and traffic to different LN. In tissues, RTE receive signals needed to become mature naïve T cells (MN, blue) and traffic through lymphoid tissues and blood. A fraction of MN upregulate CD69 (darker blue) and are potentially retained in LN sites while RTE and MN may migrate freely throughout lymphoid tissue sites (e.g. LN1 to LN2). Within tissue sites, naïve T cells undergo low levels of proliferation with potential long term maintenance of naïve T cells through homeostatic proliferation in situ. Naïve T cell diversity could also be a function of the interactions of naïve T cells in tissues with dendritic cells or stromal components. Phenotypic markers of RTE and MN are indicated in the table.