**1. Introduction**

Tissue-resident memory T cells were discovered about a decade ago. Before the discovery of TRM cells and acceptance as a new subset of T cell, memory T cells have been subdivided into two populations: effector memory and central memory T cell [1, 2]. Traditionally, it was thought that T cells taken into the tissues during infection and leave the tissue after the pathogen clearance or undergo apoptosis [3]. However, at the beginning of this millennium, it was observed that some CD8+ T cells remain long-term in the tissues after infection.

The discovery of antigen-specific CD8+ T cells located in the lung after influenza virus infection was the first example of phenomenon [4]. Later, this finding was also observed in other non-lymphoid tissues after infections with Listeria and vesicular stomatitis virus [5, 6]. Eventually, TRM cells have been described in almost all organs and can be either CD4+ or CD8+ but tissue residency has been predominantly described for memory CD8+ T cells [7]. The term "TRM cells" were used to refer to CD8+ cells, unless otherwise specified in this chapter.

The retention of TRM cells is based on two mechanisms. First, TRM cells do not express lymph node homing molecules, which are required for tissue exit such as CD62L, CCR7, and S1PR1. Second TRM cells express adhesion molecules to their

host tissue such as CD103 and CD49a [8–12]. Not all of these markers are essential for TRM identification and function of many of them are still not fully understood.

The major function of TRM cells is to establish frontline defense against previously encountered pathogens in barrier tissues where they first encounter [13, 14]. Due to their robust systemic responses, TRM cells provide superior protection compared with circulating memory T cells in peripheral tissues [15–17]. However, dysregulation of TRM can contribute to human autoimmune and inflammatory diseases such as psoriasis, vitiligo, and multiple sclerosis [18–20].

In this chapter, we aimed to emphasize TRM cell location, migration, phenotypic structure, maintenance, and diseases associated with TRM cells. We discuss the TRM cells in a basic and perceptible form as a whole, where there is no unity due to a large number of tissue variations use. We have reviewed the subject not only on the molecular level, but also on the perspective of disease formation and therapeutic usage.

## **2. Location**

T cells can be distinguished based to their microenvironment or their location in the host tissues and thereby it is possible to classify them as TRM cells or other T cell subsets [21–23]. TRM cells are easily identified in the tissues that have direct exposure to the pathogens such as the gut, skin, lungs, and reproductive system, where they receive signals that are required for their unique development program from these microenvironments [20, 24–27].

TRM cells have different phenotypes that show heterogeneity depending on the host tissue microenvironment. Requirement for TRM generation, proliferation, migration, and maintenance vary in different kind of tissues [9, 25, 26]. In particular, the majority of TRM cells are CD8+ memory T cells, and the TRM cell population in the skin is known as CD103+ and Cd69+. However, CD4+ TRM cell populations have been identified in the skin, lungs, reproductive tract, and salivary glands. Similar to CD8 TRM cells, they express the surface molecules CD69 but expression of CD103 is low or negative [28–31]. These requirements will be detailed below according to tissue types.

The locations of the TRM cell can be classified according to host tissues as shown in **Figure 1**.

The skin is one of the primary barrier tissues against infectious agents. Epidermis, dermis, and subcutaneous fatty region form a 3-layer structure of the skin and

**51**

*Resident Memory T Cells*

*DOI: http://dx.doi.org/10.5772/intechopen.90334*

intraepithelial compartment [36, 37].

HIV and HPV [16, 39, 40].

studies [28, 44].

in the brain as TRM cells [50].

prognosis in various cancers [57].

TRM formation has been shown in all layers [32–34]. The skin has very complex cell populations and hosts both natural and adaptive immune system cells. These immune system cells provide a biological barrier to invasive pathogens. CD8+ TRM constitutes the majority of the memory T cell population in the epidermis. CD8+ TRM cells are commonly resident in the skin and their numbers increase rapidly when they are exposed with the infectious agents. Skin TRM cells may easily characterized due to their surface markers such as marker CD69, CD103, and CD49a [9, 27, 35]. These

The intestinal mucosa consists of a layer of single epithelial cells and provides a barrier tissue against infectious agents. This layer is also considered as an immunological site for the maintenance of TRM cells. Following intestinal infections, a significant number of pathogen-specific TRM cells have been shown to form in the

The female reproductive tract (FRT) is another organ that is directly exposed to external pathogens. FGT can be divided into two parts. Upper female reproductive tract consists of endometrium and endocervix and lower FRT consists of vagina and ectocervix. FRT is a variable tissue that undergoes significant cyclic changes in women. Under the control of estrogen and progesterone hormones, growth, differentiation, and degeneration occurs periodically [38, 39]. Although this suggests that anatomical sites are limited for the localization of TRM cells, it has been showed that numerous immune system cells, including memory T cells are present throughout FRT. Generation of FRT TRM cells is a promising vaccination strategy against HSV-2, and potentially against other sexually transmitted infections such as

Respiratory tract (RT) is also a structure which is directly exposed to external pathogens. RT can also be divided into two parts as upper (URT) and lower (LRT). Most common airborne pathogens in humans primarily infect URT [41, 42]. URT contains lymph nodes known as tonsils, which contain B cell follicles and T cell subsets. URT is considered a mucosal inductive region for humoral and cellular immune responses. Although the effector CD4+ T cells predominate the tonsils, the presence and the localization of TRM cells is also shown in the lungs [15, 43]. Salivary glands are exocrine epithelial tissues, which are the targets of viral infections. The presence of TRM cells in these tissues has also been shown in various

The liver is an organ, which is the member of the immune system. Through the portal vein, antigen-rich blood enters the liver and encounters the immune system cells that are resident in the tissue [22, 45, 46]. Studies have shown that CD8+ TRM cells are established in the liver especially after systemic infection or vaccination [47, 48].

Due to the presence of a blood-brain barrier, immune cells are not thought to be resident in the central nervous system [49]. However, after clearing a viral infection in the central nervous system, some of the antigen-specific CD8+ T cells maintained

The kidney has a very high amount of blood vessels and has a very high circulating volume. This helps to eliminate toxins from the body. Therefore, healthy kidneys are not suitable tissues for the localization of immune system cells. Even so, it has been shown that a small number of resident TRM cells may be present in the kidney. White adipose tissue is another tissue in which TRM cells have been shown

CD8+ TRM cells have been reported in solid tumors [54]. Studies have shown that infiltrating T lymphocytes (TIL) are phenotypically similar to TRM cells that TRM cells from neighboring peripheral tissues could infiltrate into solid tumors [55, 56]. It was found that presence of CD8+ TRM cells is associated with good

to be resident and they act as a reservoir of TRM cells [51–53].

markers and others will be described in detail in terms of their function.

**Figure 1.**

*Classification of TRM cell locations according to their host tissue.*

#### *Resident Memory T Cells DOI: http://dx.doi.org/10.5772/intechopen.90334*

*Cells of the Immune System*

**2. Location**

in **Figure 1**.

host tissue such as CD103 and CD49a [8–12]. Not all of these markers are essential for TRM identification and function of many of them are still not fully understood. The major function of TRM cells is to establish frontline defense against previously encountered pathogens in barrier tissues where they first encounter [13, 14]. Due to their robust systemic responses, TRM cells provide superior protection compared with circulating memory T cells in peripheral tissues [15–17]. However, dysregulation of TRM can contribute to human autoimmune and inflammatory

In this chapter, we aimed to emphasize TRM cell location, migration, phenotypic structure, maintenance, and diseases associated with TRM cells. We discuss the TRM cells in a basic and perceptible form as a whole, where there is no unity due to a large number of tissue variations use. We have reviewed the subject not only on the molecular level, but also on the perspective of disease formation and therapeutic usage.

T cells can be distinguished based to their microenvironment or their location in the host tissues and thereby it is possible to classify them as TRM cells or other T cell subsets [21–23]. TRM cells are easily identified in the tissues that have direct exposure to the pathogens such as the gut, skin, lungs, and reproductive system, where they receive signals that are required for their unique development program

TRM cells have different phenotypes that show heterogeneity depending on the host tissue microenvironment. Requirement for TRM generation, proliferation, migration, and maintenance vary in different kind of tissues [9, 25, 26]. In particular, the majority of TRM cells are CD8+ memory T cells, and the TRM cell population in the skin is known as CD103+ and Cd69+. However, CD4+ TRM cell populations have been identified in the skin, lungs, reproductive tract, and salivary glands. Similar to CD8 TRM cells, they express the surface molecules CD69 but expression of CD103 is low or negative [28–31]. These requirements will be detailed

The locations of the TRM cell can be classified according to host tissues as shown

The skin is one of the primary barrier tissues against infectious agents. Epidermis,

dermis, and subcutaneous fatty region form a 3-layer structure of the skin and

diseases such as psoriasis, vitiligo, and multiple sclerosis [18–20].

from these microenvironments [20, 24–27].

*Classification of TRM cell locations according to their host tissue.*

below according to tissue types.

**50**

**Figure 1.**

TRM formation has been shown in all layers [32–34]. The skin has very complex cell populations and hosts both natural and adaptive immune system cells. These immune system cells provide a biological barrier to invasive pathogens. CD8+ TRM constitutes the majority of the memory T cell population in the epidermis. CD8+ TRM cells are commonly resident in the skin and their numbers increase rapidly when they are exposed with the infectious agents. Skin TRM cells may easily characterized due to their surface markers such as marker CD69, CD103, and CD49a [9, 27, 35]. These markers and others will be described in detail in terms of their function.

The intestinal mucosa consists of a layer of single epithelial cells and provides a barrier tissue against infectious agents. This layer is also considered as an immunological site for the maintenance of TRM cells. Following intestinal infections, a significant number of pathogen-specific TRM cells have been shown to form in the intraepithelial compartment [36, 37].

The female reproductive tract (FRT) is another organ that is directly exposed to external pathogens. FGT can be divided into two parts. Upper female reproductive tract consists of endometrium and endocervix and lower FRT consists of vagina and ectocervix. FRT is a variable tissue that undergoes significant cyclic changes in women. Under the control of estrogen and progesterone hormones, growth, differentiation, and degeneration occurs periodically [38, 39]. Although this suggests that anatomical sites are limited for the localization of TRM cells, it has been showed that numerous immune system cells, including memory T cells are present throughout FRT. Generation of FRT TRM cells is a promising vaccination strategy against HSV-2, and potentially against other sexually transmitted infections such as HIV and HPV [16, 39, 40].

Respiratory tract (RT) is also a structure which is directly exposed to external pathogens. RT can also be divided into two parts as upper (URT) and lower (LRT). Most common airborne pathogens in humans primarily infect URT [41, 42]. URT contains lymph nodes known as tonsils, which contain B cell follicles and T cell subsets. URT is considered a mucosal inductive region for humoral and cellular immune responses. Although the effector CD4+ T cells predominate the tonsils, the presence and the localization of TRM cells is also shown in the lungs [15, 43].

Salivary glands are exocrine epithelial tissues, which are the targets of viral infections. The presence of TRM cells in these tissues has also been shown in various studies [28, 44].

The liver is an organ, which is the member of the immune system. Through the portal vein, antigen-rich blood enters the liver and encounters the immune system cells that are resident in the tissue [22, 45, 46]. Studies have shown that CD8+ TRM cells are established in the liver especially after systemic infection or vaccination [47, 48].

Due to the presence of a blood-brain barrier, immune cells are not thought to be resident in the central nervous system [49]. However, after clearing a viral infection in the central nervous system, some of the antigen-specific CD8+ T cells maintained in the brain as TRM cells [50].

The kidney has a very high amount of blood vessels and has a very high circulating volume. This helps to eliminate toxins from the body. Therefore, healthy kidneys are not suitable tissues for the localization of immune system cells. Even so, it has been shown that a small number of resident TRM cells may be present in the kidney. White adipose tissue is another tissue in which TRM cells have been shown to be resident and they act as a reservoir of TRM cells [51–53].

CD8+ TRM cells have been reported in solid tumors [54]. Studies have shown that infiltrating T lymphocytes (TIL) are phenotypically similar to TRM cells that TRM cells from neighboring peripheral tissues could infiltrate into solid tumors [55, 56]. It was found that presence of CD8+ TRM cells is associated with good prognosis in various cancers [57].

#### *Cells of the Immune System*

Secondary lymphoid organs and lymph nodes are the tissues where TCM and TEM cells are more common and pass through. However, recent studies have shown that a small number of non-circulating memory T cells are present in these tissues. TRM cells in SLO show phenotypic characterization similar to those in non-lymphoid tissues [1, 58].

Primary lymphoid organs (PLO) are bone marrow and thymus. Antigen-specific TRM cells have also been found in these tissues and have been shown to facilitate long-term maintenance in the PLO. TRM cells in the PLO express CD69 and CD103 as a characteristic of TRM phenotype [59–61].
