Armed and Ready: Transcriptional Regulation of Tissue-Resident Memory CD8 T Cells

Abstract

A fundamental benefit of immunological memory is the ability to respond in an enhanced manner upon secondary encounter with the same pathogen. Tissue-resident memory CD8 T (T_RM) cells contribute to improved protection against reinfection through the generation of immediate effector responses at the site of pathogen entry. Key to the potential of T_RM cells to develop rapid recall responses is their location within the epithelia of the skin, lungs, and intestines at prime entry sites of pathogens. T_RM cells are among the first immune cells to respond to pathogens that have been previously encountered in an antigen-specific manner. Upon recognition of invading pathogens, T_RM cells release IFN-γ and other pro-inflammatory cytokines and chemokines. These effector molecules activate the surrounding epithelial tissue and recruit other immune cells including natural killer (NK) cells, B cells, and circulating memory CD8 T cells to the site of infection. The repertoire of T_RM effector functions also includes the direct lysis of infected cells through the release of cytotoxic molecules such as perforin and granzymes. The mechanisms enabling T_RM cells to respond in such a rapid manner are gradually being uncovered. In this review, we will address the signals that instruct T_RM generation and maintenance as well as the underlying transcriptional network that keeps T_RM cells in a deployment-ready modus. Furthermore, we will discuss how T_RM cells respond to reinfection of the tissue and how transcription factors may control immediate and proliferative T_RM responses.

Keywords: BLIMP-1; Notch; RUNX3; T cell diferentiation; homolog of Blimp-1 in T cells; secondary responses; tissue-resident memory T cells; transcription factors.

Figure 1

General features of tissue-resident memory CD8 T (T_RM) cells. Generation and maintenance of T_RM cells is regulated by a distinct set of transcription factors, including Runx3, Blimp-1, and its homolog of Blimp-1 in T cells as well as the transcriptional activator Notch. These transcription factors instruct a tissue-residency program that allows for the long-term retention and maintenance of T_RM cells within peripheral tissues. T_RM cells across tissues maintain expression of CD69, which promotes tissue residency by interfering with spingosine-1 phosphate receptor (S1PR1) function. S1PR1 mediates egress of T cells into the circulation and its downregulation is a core characteristic of T_RM cells. In many tissues, T_RM cells also express high levels of CD49a, an adhesion molecule binding to collagen (in complex with β1 integrin) to establish tissue residency. The α_E integrin CD103 is expressed by mucosal T_RM cells and may contribute to tissue retention by interaction with E-cadherin on the surrounding epithelial cells. In liver sinusoids, local T_RM cells upregulate LFA-1, which supports their tissue residence by binding to ICAM-1 on liver sinusoidal endothelial cells. In addition to these adhesion molecules, T_RM cells in many tissues are characterized by elevated transcript levels encoding for pro-inflammatory cytokines, e.g., IFN-γ and TNF-α, and protein expression of the cytotoxic serine protease granzyme B. Abbreviations: Runx3, Runt-related transcription factor 3; Blimp-1, B lymphocyte-induced maturation protein-1; Hobit, homolog of Blimp-1 in T cells; RBPJ, recombining binding protein suppressor of hairless; LFA-1, lymphocyte function-associated antigen-1; ICAM-1, intercellular adhesion molecule 1; IFN-γ, interferon γ; TNF-α, tumor necrosis factor α.

Figure 2

Protective effector responses of epithelial T_RM cells upon secondary infection. T_RM cells in the epithelia continually patrol their local environment, projecting dendritic extensions in multiple directions. Upon pathogen challenge and antigen re-encounter, T_RM cells rapidly release pro-inflammatory cytokines, including IFN-γ, TNF-α, and IL-2, which induce several immune cell- and tissue-specific effects. Local cytokine release by T_RM cells results in recruitment and activation of natural killer (NK) cells and dendritic cells (DCs), as well as upregulation of VCAM-1 on endothelial cells in local blood vessels, which may enhance the recruitment of T_CM, T_EM, and B cells from the circulation. T_RM cell reactivation and cytokine release also induces a tissue-wide state of alert, resulting in upregulation of many innate immune response genes, including interferon-induced transmembrane protein 3 (IFITM3), and the increased local expression of inflammatory chemokines. The protective capacity of T_RM cells may also rely on perforin-mediated killing of target cells. One to two days after antigen re-encounter, T_RM cells undergo local proliferation. Further investigation is required to determine whether T_RM cells exit their local environment after reactivation. Abbreviations: IFN-γ, interferon γ; TNF-α, tumor necrosis factor α; IL-2, interleukin 2; ICAM-1, vascular cell adhesion molecule 1; T_CM cell, central memory T cell; T_EM cell, effector memory T cell; CCL, C-C motif chemokine; CXCL9, C-X-C motif chemokine 9.

Figure 3

Transcriptional regulation of T_RM cells during development, maintenance, and upon pathogen re-challenge. (A) During their formation, T_RM cells receive multiple signals from the tissue microenvironment that integrate into a transcriptional program, which drives T_RM differentiation and maintenance. In several tissues, transforming growth factor β (TGF-β) signaling drives the downregulation of the T-box transcription factors Eomesodermin (Eomes) and T-bet. Residual T-bet expression is required for IL-15Rβ expression. The transcription factor homolog of Blimp-1 in T cells (Hobit) can be induced in an IL-15-dependent manner and, together with its homolog Blimp-1, represses the expression of S1PR1, CCR7, Krϋpple-like factor 2 (KLF2), and TCF-1, which is crucial for tissue residency. Blimp-1 and Hobit may also contribute to granzyme B maintenance in T_RM cells. The transcription factor Runx3, which can be induced by TGF-β signaling, is crucial for the establishment and maintenance of many aspects of T_RM cells, including granzyme B and CD103 expression. Runx3 has been shown to induce Blimp-1. Notch may regulate expression of the adhesion molecule CD103, is essential for maintenance of T_RM cells and might contribute to the elevated transcript levels encoding for pro-inflammatory cytokines in T_RM cells. Other factors regulating T_RM cells include the nuclear receptor NR4A1, and the aryl hydrocarbon receptor (AhR). During quiescence, T_RM cells show low proliferative activity. (B) Following pathogen re-encounter, T_RM cells are exposed to antigen-dependent T cell receptor (TCR) triggering and a variety of inflammatory signals. TCR triggering in T_RM cells may result in downregulation of Hobit, thereby weakening its contribution to maintenance of tissue residency. Inflammatory signals, such as IL-12 and type I interferons (IFN), can induce expression of Blimp-1 and T-bet. While increased Blimp-1 expression might fortify T_RM features, elevated levels of T-bet could interfere with tissue residency. T_RM cells rapidly release pro-inflammatory cytokines upon reactivation in an antigen-dependent manner. Upon re-infection, T_RM cells undergo local proliferation. Dashed lines indicate relations that require further investigation. Abbreviations: Blimp-1, homolog of B lymphocyte-induced maturation protein 1; IL, interleukin; S1PR1, sphingosine-1-phosphate receptor 1; CCR7, C-C chemokine receptor type 7; TCF-1, T cell factor 1; Runx3, Runt-related transcription factor 3; RBPJ, recombining binding protein suppressor of hairless; NR4A1, nuclear receptor subfamily 4 group A 1.