**5. Phenotype**

*Cells of the Immune System*

interstitium [9, 35, 82].

**4.4 CD44**

*4.4.1 Parabiosis*

is in equilibrium with the other.

*4.4.3 Organ transplantation*

*4.4.2 Bone marrow chimera (BMC)*

transferred to the recipient organism [87, 88].

Collagen IV enriched in the basement membrane separating epidermis and dermis. CD49a is therefore a good marker for skin TRM cells. In human skin epithelia, CD8+ CD49a+ TRM cells produced interferon-γ, whereas CD8+ CD49a TRM cells produced interleukin-17 (IL-17). It has been reported that CD8+ T cells with a TRM phenotypes (CD103+ and CD49a+) are present in solid tumors as well as lung

VLA1 is a receptor not only involved in adhesion but also to migration and survival. In the formation and proliferation of TRM cells, CD49a together with CD103

The CD44 antigen is a cell-surface glycoprotein involved in cell-cell interactions, cell adhesion, and migration [83]. The most well-studied function of CD44 is as a receptor for hyaluronic acid, a component of the extracellular matrix. In regard to accessing peripheral tissues during an immune challenge, CD44 can bind hyaluronic acid expressed on vascular endothelial cells and facilitate transmigration. CD44 is a classical marker of previous activation, expressed on newly generated

It is important to specify that TRM cells express different markers depending on the host tissues. It should not be ignored that there may be some differences between TRM subsets in various tissue types. The results obtained by using in vivo techniques such as parabiosis, organ transplantation, using transgenic mice, and bone marrow chimera techniques were more effective in the identification TRM cell proliferation. The main factors that enable scientists to identify TRM cells as a

Parabiosis is a surgical process that allows the sharing of blood circulation in two organisms. Bringing the skin of the two animals, in particular mice, together stimulate the capillary blood vessel formation in this region. Blood and immune cells circulate between parabiotic partners [86]. Therefore, migration or residence can be examined by investigating whether the immune system cell in one organism

BMC is another widely used technique to study donor organism, which has congenitally distinctive or labeled bone marrow, and a recipient organism, which have been irradiated, thus losing its all bone marrow-derived cells (lymphocytes) are two component of this method. Then, bone marrow cells of donor organism are

Transplantation is a similar approach to BMC in TRM cell studies. In this method, organ or skin graft of the donor organism is transplanted into the recipient. The equilibrium between the established T cell populations of donor and recipient organisms are examined to investigate the TRM cells. Moreover, TRM cells

have important roles in organ transplantation and tissue rejection [89, 90].

and CD69 are the most determinative markers of TRM presence.

effector cells as well as resting memory cells [23, 84, 85].

subset of T cells have been obtained by these methods.

**54**

There is not a single phenotypic character to be used to identify TRM cells. Many researchers have examined the TRM cell phenotype in different tissues including lungs, liver, lymphoid sites, skin, and intestines both in mice and humans.

Characteristically, TRM cells express CD103 and CD69. CD49a, which binds to the extracellular collagen and laminin, can be added to these two for the skin tissue [21, 23, 93]. TRM cells do not express or express very low levels of lymph node homing molecules which are required for tissue exit such as CD62L, CCR7, and S1PR1 and it is critical for TRM cell tissue residency [1, 15, 53, 67, 69]. S1P1 is mediated by the downregulation of the transcription factor KLF2 [93].

TRM cells also express cluster of chemokines and chemokine receptors including CXCR3 and CCR6, and was able to produce chemokine ligands such as CCL19 andCCL21 [2, 93, 94].

Tissue microenvironment also promotes TRM differentiation. TRM precursors that are KLRG1 negative, are more likely to differentiate into TRM cells [53, 55].

Broad range of transcription factors is associated with TRM formation. Most common transcription factors are AHR (aryl hydrocarbon receptor), Notch, Blimb1, Hobit, Eomes, and T-bet [30, 95]. These phenotypic structures are illustrated in **Figure 3** and each is described in detail in **Table 1**.


#### **Figure 3.**

*Schematic illustration of some of the most common, receptors, transcription factors, ligands, and molecules involved in differentiation and maintenance of TRM cells and their regulation for TRM formation.*


#### **Table 1.**

*Detailed explanations of receptors, transcription factors, ligands, and molecules involved in formation and migration of TRM.*

### **6. TRM and diseases**

TRM cells may assume pathogenic roles if they become over-sensitized or autoreactivated. However, TRM cells are the first line protector of the immune system against the pathogen at the same time. Therefore, they play or stimulate to play an important role in effective treatment or vaccination. **Figure 4** summarizes the diseases associated with TRM cells both in the perspectives of pathogenic and protective roles.

**57**

*Resident Memory T Cells*

**6.1 Pathogenic roles**

immune cells in mouse models [110].

interleukin-23 (IL-23) and IL-17 in psoriasis [41, 112].

*Illustration of some of the TRM-associated diseases that has been reported.*

leading to depigmentation of the skin [73].

Psoriasis is a common chronic inflammatory skin disease with a spectrum of clinical phenotypes and results from the interplay of genetic, environmental, and immunological factors [107]. Psoriasis can be divided into five types. The most common is plaque psoriasis, which causes itching and pain due to plaque formation. This type also maintains large areas of erythema or scaling of the skin, causing deformation of the skin [108]. Many studies showed that the chronic inflammation observed in psoriasis arises from an uncontrolled proliferation of T cells [66, 109]. Resident T cells play a role in the formation and recurrence of psoriatic lesions. Psoriasis lesion can be triggered and sustained by the local network of skin-resident

In recent studies, TRM cells were identified in healthy skin but were increased in psoriatic lesions. And these TRM cells have been found to produce perforin and IFN-gamma and to secrete IL-17 which is responsible for unwanted symptoms [111]. Demarcated, inflamed, and hyperproliferative plaques are maintained by

For the treatment of psoriasis, an autoimmune disease, various immunosuppressive drugs, neutralizing antibodies, and cytokines have been tried for the treatment [42, 113–116]. These therapies have not been fully successful nowadays due to the systemic side-effects and the presence of autoreactive resident T cells in tissues

Another disease with several patchy appearance lesions in the skin like psoriasis is Vitiligo. These two diseases are often confused with each other. Vitiligo is an autoreactive T cell-mediated disease in which immune cells target and kill melanocytes,

Vitiligo lesions recur in the same areas of the skin and this is a sign of the presence of resident autoimmune memory [117]. Recent studies have shown the presence of melanocyte-specific TRM cells in skin tissues with vitiligo. These TRM

*6.1.1 Psoriasis*

**Figure 4.**

without lesions.

*6.1.2 Vitiligo*

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

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

#### **Figure 4.**

*Cells of the Immune System*

Krüppel-like Factor 2

Killer cell lectin-like receptor subfamily G member 1 (KLRG1)

C-C chemokine receptor type 7 (CCR7)

Sphingosine-1 phosphate receptor 1

Chemokine receptor 3

Chemokine ligand 21

(S1PR1)

(CXCR3)

(CCL21)

Eomesodermin (Eomes) and T-bet

Aryl hydrocarbon receptor (Ahr)

*migration of TRM.*

**Table 1.**

(KLF2)

**56**

**6. TRM and diseases**

TRM cells may assume pathogenic roles if they become over-sensitized or autoreactivated. However, TRM cells are the first line protector of the immune system against the pathogen at the same time. Therefore, they play or stimulate to play an important role in effective treatment or vaccination. **Figure 4** summarizes the diseases associated

**Marker Function Regulation**

activation antigen whose rapid expression makes it amenable for the early detection of T-cell activation and for subset activation

widely used as a proliferation marker that is expressed by cells mitotic

CCR7 is a chemokine receptor which regulates T cell trafficking and compartmentalization within secondary lymphoid organs [103]

Klf2 also plays a role in T-cell differentiation and regulate the migration of mature thymocytes from the thymus and to control the circulation of peripheral T cells. In the absence of Klf2, mature T cells exist in an activated state and are more prone to apoptosis [98]

KLRG1 is expressed by NK and T-cell subsets and recognizes members of the classical cadherin family. KLRG1 is widely used as a lymphocyte differentiation marker in both humans and mice [102]

S1PR1 was implicated in lymphocyte trafficking and it has an important role in regulating endothelial cell cytoskeletal structure,

CXCR3 plays a role to regulate leukocyte trafficking. Ligand that binds to CXCR3 induces cellular responses, such as integrin activation, cytoskeletal changes and chemotactic migration [94]

of leukocytes at sites of inflammation and the recirculation of lymphocytes between blood and lymphoid tissues [105]

Downregulation of T-bet and Eomes enables increased TGF-β responsiveness, thereby creating a feedback loop that promotes TRM

CCL21 is a high affinity functional ligand for chemokine receptor

combination enforces tissue retention by depression of KLF2, S1PR1,

is required for long-term persistence of TRM as a survival pathway for

↑

↑

↑

↓

↓

↑

↓

↓

↑

↓

↓

↓

↑

↑

↑

CD103 (integrin αEβ7) CD103 is as a receptor for E-cadherin, an adherent junctional protein interlocking epithelial cells [96]

CD49a (integrin α1β1) CD49a pairs with CD29 (integrin β1) to form the heterodimer called VLA-1 which is a collagen-binding integrin [35]

CD69 Human transmembrane C-Type lectin protein. CD69 is a lymphoid

Ki67 Function of the Ki67 protein is still unclear. Ki67 protein has been

migration, and T cell maturation [104]

CD62L (L-selectin) L-selectin is an adhesion molecule that regulates both the migration

Blimp-1 and Hobit Loss incompatible with development of tissue-resident cell types; in

T cells residing in the epidermis [33]

Notch Required for maintenance of CD8 TRM; proposed to control metabolic functions in TRM and CD103 expression [23]

*Detailed explanations of receptors, transcription factors, ligands, and molecules involved in formation and* 

analyses [97]

phases [99–101]

7 [106]

differentiation [30]

and CCR7 [69]

with TRM cells both in the perspectives of pathogenic and protective roles.

*Illustration of some of the TRM-associated diseases that has been reported.*

#### **6.1 Pathogenic roles**

#### *6.1.1 Psoriasis*

Psoriasis is a common chronic inflammatory skin disease with a spectrum of clinical phenotypes and results from the interplay of genetic, environmental, and immunological factors [107]. Psoriasis can be divided into five types. The most common is plaque psoriasis, which causes itching and pain due to plaque formation. This type also maintains large areas of erythema or scaling of the skin, causing deformation of the skin [108]. Many studies showed that the chronic inflammation observed in psoriasis arises from an uncontrolled proliferation of T cells [66, 109]. Resident T cells play a role in the formation and recurrence of psoriatic lesions. Psoriasis lesion can be triggered and sustained by the local network of skin-resident immune cells in mouse models [110].

In recent studies, TRM cells were identified in healthy skin but were increased in psoriatic lesions. And these TRM cells have been found to produce perforin and IFN-gamma and to secrete IL-17 which is responsible for unwanted symptoms [111]. Demarcated, inflamed, and hyperproliferative plaques are maintained by interleukin-23 (IL-23) and IL-17 in psoriasis [41, 112].

For the treatment of psoriasis, an autoimmune disease, various immunosuppressive drugs, neutralizing antibodies, and cytokines have been tried for the treatment [42, 113–116]. These therapies have not been fully successful nowadays due to the systemic side-effects and the presence of autoreactive resident T cells in tissues without lesions.

#### *6.1.2 Vitiligo*

Another disease with several patchy appearance lesions in the skin like psoriasis is Vitiligo. These two diseases are often confused with each other. Vitiligo is an autoreactive T cell-mediated disease in which immune cells target and kill melanocytes, leading to depigmentation of the skin [73].

Vitiligo lesions recur in the same areas of the skin and this is a sign of the presence of resident autoimmune memory [117]. Recent studies have shown the presence of melanocyte-specific TRM cells in skin tissues with vitiligo. These TRM cells are CD8+ cells secreting IFNg and TNFα and expressing common TRM markers such as CD69, CD103, and CXCR3 [19, 118]. In a mouse vitiligo model, it was showed that neutralization of the IL-15 receptor by anti-CD122 antibody decreases the IFNg production from TRM cells and leads to repigmentation of the lesion [91]. Currently, there is no FDA-approved vitiligo treatment and such studies targeting TRM cells are likely to have prosperous results in the future.

### *6.1.3 Multiple sclerosis*

Multiple sclerosis (MS) is a chronic, immune-mediated, demyelinating disorder of the central nervous system [119]. The brain is not a frequently visited tissue for immune cells due to its barriers. In one of the few studies in this field, CD8+ TRM cells that persist within the brain after an acute systemic vesicular stomatitis virus infection were characterized [120]. These cells were not in equilibrium with circulating T cells as evidence for TRM establishment in the brain tissue [50]. However, the mechanism for the generation and maintenance of TRM cells in the brain remains unclear.

### *6.1.4 Asthma*

Asthma, other allergic airway diseases are inflammatory lung diseases that are related to the TRM cells. Asthma is a heterogeneous disease and is characterized by chronic airway inflammation, increased susceptibility to respiratory viral infection, and altered airway microbiology [121, 122]. The lungs have been widely investigated for TRM cell formation due to their exposure to the external environment and recurrent infections. In one of those studies, house dust mite HDM-specific memory cells have been identified as central memory cells in the lymphoid organs and TRM cells in the lung [123].

The majority of T cells in the human lung are TRM cells. TRM cells provide important roles in the protection against asthma, multiple respiratory pathogens, and other allergic diseases and might be contributed for developing new therapies and vaccines [25, 26].

### *6.1.5 Rheumatoid arthritis*

Rheumatoid arthritis is a chronic autoimmune disease which can cause cartilage and bone damage, progressive articular damage, as well as functional loss disability [124–126]. Rheumatoid arthritis, is known largely a disease of the joints, however many organs and systems are effected, including the pulmonary, cardiovascular, ocular, and cutaneous systems [127].

Recurrence of arthritis in the joints is the key for the treatment of human rheumatoid arthritis. The disease is propagated through resident cells in the synovium of the joint, resident synovial cells that interact with the infiltrating immune cells and transition from acute synovitis to chronic RA [128]. The link between recurrence and residency suggests the presence of TRM cells. Studies have shown that TRM formation was induced in the enthesis. The enthesis is the region at the junction between tendon and bone. This zone was shown to contain a unique population of resident T cells, when activated by the cytokine interleukin-23 and can cause pathogenesis [129, 130].

#### *6.1.6 Crohn's disease*

Crohn disease (CD) is an inflammatory condition of the gastrointestinal (GI) tract, characterized by unpredictable periods of symptomatic relapses and

**59**

*Resident Memory T Cells*

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

and TRM formation should be investigated.

mediated treatment and vaccination strategies.

needs to be further investigated.

strategies can be developed [135].

where they first contact [40].

**6.2 Protective roles**

remissions [131]. It has been suggested that CD has clinical similarities with TRMmediated skin diseases. The skin lesion is similar "skip lesions" in the gut seen in CD [3, 67]. The use of immunosuppressive drugs for the treatment of CD can be considered as another similarity. However, the presence of a direct link between CD

Some of the other diseases that are related to the TRM formation are mycosis fungoides, contact dermatitis, chronic eczema, and fixed drug eruption and all

Autoreactive TRM cells may contribute to the pathogenesis of autoimmune, atopic, and allergic diseases as described above. In contrast, they can provide rapid and efficient protection against wide range of pathogens and various types of tumors. Malaria, HSV, and cancer must be emphasized due to the role of TRM cell

Malaria is a vector-borne parasitic tropical disease found in 91 countries worldwide [132]. *Plasmodium falciparum* (PF) is the dominant specie that produces high levels of parasites in critical organs and cause severe anemia, especially in African children, in whom. Malaria affected an estimated 216 million people causing 445,000 deaths in 2016 [133] around the World and the vast majority of malaria deaths occur in developing countries. Over the years, extensive research has been conducted on the prevention and treatment of malaria. However, increasing drug and insecticide resistance and threatens the successes. Moreover, the results obtained from current vaccine studies have not been sufficient to prevent malaria. Development of a broadly protective vaccine is required for the eradication of Malaria. For this purpose, TRM cell-mediated vaccination strategies can be very promising. Researchers identified that memory CD8+ T cells that expressed the gene signature of TRM cells and remained permanently within the liver [45, 48]. A recent study explored the mechanism of action of a newly developed malaria vaccine, *Plasmodium falciparum* sporozoites (PfSPZ), which has exhibited very promising efficacy in human clinical trials. The efficacy of this vaccine has been shown to be due to TRM formation within the liver was 100-fold higher [47]. Researcher also showed that this TRM cells within the liver can also be generated by

a "prime and trap" or "prime and pull" vaccination strategy [16, 22].

This strategy has two stages. First is the conventional vaccination to obtain systemic T cell responses (prime), second is recruitment of activated T cells via topical chemokine application to the desired tissue (pull), where such TRM cells were established and mediate long-term protective immunity [16, 102, 134]. The robust protective immunity provided by memory T cells localized in peripheral tissues, together with localized memory T cells, provides hope that site-specific vaccination

Development of a T cells mediated vaccines are required for efficacious protection. Due to their robust systemic responses, TRM cells provide superior protection compared with circulating memory T cells in peripheral tissues [136]. Recent studies focused on TRM establishment of training to protect against infection agent

The female genital tract, which is a portal of entry for sexually transmitted infections such as HIV and HSV. In a recent study "prime and pull" strategy was used against HSV-2 infection in female genital tract. In this study, mice were infected by attenuated strain of HSV-2 subcutaneously and topical application of chemokines CXCL9 and CXCL10 have been used to recruit TRM cells in the vagina

to prevent the development of clinical disease for further infections [16].

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

remissions [131]. It has been suggested that CD has clinical similarities with TRMmediated skin diseases. The skin lesion is similar "skip lesions" in the gut seen in CD [3, 67]. The use of immunosuppressive drugs for the treatment of CD can be considered as another similarity. However, the presence of a direct link between CD and TRM formation should be investigated.

Some of the other diseases that are related to the TRM formation are mycosis fungoides, contact dermatitis, chronic eczema, and fixed drug eruption and all needs to be further investigated.

#### **6.2 Protective roles**

*Cells of the Immune System*

*6.1.3 Multiple sclerosis*

*6.1.4 Asthma*

and TRM cells in the lung [123].

and vaccines [25, 26].

*6.1.5 Rheumatoid arthritis*

pathogenesis [129, 130].

*6.1.6 Crohn's disease*

ocular, and cutaneous systems [127].

cells are CD8+ cells secreting IFNg and TNFα and expressing common TRM markers such as CD69, CD103, and CXCR3 [19, 118]. In a mouse vitiligo model, it was showed that neutralization of the IL-15 receptor by anti-CD122 antibody decreases the IFNg production from TRM cells and leads to repigmentation of the lesion [91]. Currently, there is no FDA-approved vitiligo treatment and such studies targeting

Multiple sclerosis (MS) is a chronic, immune-mediated, demyelinating disorder of the central nervous system [119]. The brain is not a frequently visited tissue for immune cells due to its barriers. In one of the few studies in this field, CD8+ TRM cells that persist within the brain after an acute systemic vesicular stomatitis virus infection were characterized [120]. These cells were not in equilibrium with circulating T cells as evidence for TRM establishment in the brain tissue [50]. However, the mechanism for

Asthma, other allergic airway diseases are inflammatory lung diseases that are related to the TRM cells. Asthma is a heterogeneous disease and is characterized by chronic airway inflammation, increased susceptibility to respiratory viral infection, and altered airway microbiology [121, 122]. The lungs have been widely investigated for TRM cell formation due to their exposure to the external environment and recurrent infections. In one of those studies, house dust mite HDM-specific memory cells have been identified as central memory cells in the lymphoid organs

The majority of T cells in the human lung are TRM cells. TRM cells provide important roles in the protection against asthma, multiple respiratory pathogens, and other allergic diseases and might be contributed for developing new therapies

Rheumatoid arthritis is a chronic autoimmune disease which can cause cartilage and bone damage, progressive articular damage, as well as functional loss disability [124–126]. Rheumatoid arthritis, is known largely a disease of the joints, however many organs and systems are effected, including the pulmonary, cardiovascular,

Recurrence of arthritis in the joints is the key for the treatment of human rheumatoid arthritis. The disease is propagated through resident cells in the synovium of the joint, resident synovial cells that interact with the infiltrating immune cells and transition from acute synovitis to chronic RA [128]. The link between recurrence and residency suggests the presence of TRM cells. Studies have shown that TRM formation was induced in the enthesis. The enthesis is the region at the junction between tendon and bone. This zone was shown to contain a unique population of resident T cells, when activated by the cytokine interleukin-23 and can cause

Crohn disease (CD) is an inflammatory condition of the gastrointestinal (GI) tract, characterized by unpredictable periods of symptomatic relapses and

the generation and maintenance of TRM cells in the brain remains unclear.

TRM cells are likely to have prosperous results in the future.

**58**

Autoreactive TRM cells may contribute to the pathogenesis of autoimmune, atopic, and allergic diseases as described above. In contrast, they can provide rapid and efficient protection against wide range of pathogens and various types of tumors. Malaria, HSV, and cancer must be emphasized due to the role of TRM cell mediated treatment and vaccination strategies.

Malaria is a vector-borne parasitic tropical disease found in 91 countries worldwide [132]. *Plasmodium falciparum* (PF) is the dominant specie that produces high levels of parasites in critical organs and cause severe anemia, especially in African children, in whom. Malaria affected an estimated 216 million people causing 445,000 deaths in 2016 [133] around the World and the vast majority of malaria deaths occur in developing countries. Over the years, extensive research has been conducted on the prevention and treatment of malaria. However, increasing drug and insecticide resistance and threatens the successes. Moreover, the results obtained from current vaccine studies have not been sufficient to prevent malaria.

Development of a broadly protective vaccine is required for the eradication of Malaria. For this purpose, TRM cell-mediated vaccination strategies can be very promising. Researchers identified that memory CD8+ T cells that expressed the gene signature of TRM cells and remained permanently within the liver [45, 48].

A recent study explored the mechanism of action of a newly developed malaria vaccine, *Plasmodium falciparum* sporozoites (PfSPZ), which has exhibited very promising efficacy in human clinical trials. The efficacy of this vaccine has been shown to be due to TRM formation within the liver was 100-fold higher [47]. Researcher also showed that this TRM cells within the liver can also be generated by a "prime and trap" or "prime and pull" vaccination strategy [16, 22].

This strategy has two stages. First is the conventional vaccination to obtain systemic T cell responses (prime), second is recruitment of activated T cells via topical chemokine application to the desired tissue (pull), where such TRM cells were established and mediate long-term protective immunity [16, 102, 134]. The robust protective immunity provided by memory T cells localized in peripheral tissues, together with localized memory T cells, provides hope that site-specific vaccination strategies can be developed [135].

Development of a T cells mediated vaccines are required for efficacious protection. Due to their robust systemic responses, TRM cells provide superior protection compared with circulating memory T cells in peripheral tissues [136]. Recent studies focused on TRM establishment of training to protect against infection agent where they first contact [40].

The female genital tract, which is a portal of entry for sexually transmitted infections such as HIV and HSV. In a recent study "prime and pull" strategy was used against HSV-2 infection in female genital tract. In this study, mice were infected by attenuated strain of HSV-2 subcutaneously and topical application of chemokines CXCL9 and CXCL10 have been used to recruit TRM cells in the vagina to prevent the development of clinical disease for further infections [16].

TRM-mediated vaccine development researches against infectious agents are not limited to PF HSV and HIV. Moreover, vaccine studies are being carried out in order to provide first step protection against many infectious agents such as influenza, varicella, Human papillomavirus (HPV), toxoplasma, etc. [8, 38, 43, 137, 138].

In the context of TRM cells, cancer should also be emphasized. Currently, developed cancer vaccines are generally aimed for the treatment and the number of prophylactic vaccines is relatively low. Therefore, vaccination studies for the formation of TRM against cancer are very promising.

Recent studies suggest that TRM cells also play a vital part in cancer surveillance [57, 139]. It was demonstrated in many studies that TRM cells generated by vaccines can protect against tumor challenge [10, 55, 140, 141]. Formation of CD8+ T cells is one of the main objectives in cancer vaccine development against solid tumors. The type of CD8+ T cells that can migrate and localize in tumor microenvironments are TRM cells. [55]. It was found that presence of CD8+ TRM cells is associated with good prognosis in various cancers [57]. TRM cells can act in three major ways against solid tumors [73].


It is becoming increasingly clear that TRM cells play an integral role in tumor surveillance in both animal models and human cancers. However, the role of TRM cells in solid human cancers should be further investigated.

## **7. Conclusion**

The knowledge about TRM cells is at an early stage. Moreover, it has been revealed only in recent decades that TRM cells are unique subsets. It was found that TRM cells become resident by their phenotypic characteristics by adopting the microenvironment of the host tissue. TRM cells are transcriptionally, phenotypically, and functionally distinct from other circulating T cell subsets.

TRM cells have different phenotypes show heterogeneity depending on the host tissue microenvironment. Requirement for TRM generation, proliferation, migration, and maintenance vary in different kind of tissues. In order to distinguish TRM cells from other T cell subsets, in most of the studies in both mice and humans, identification markers such as CD103, CD69, and Cd49a were the most common ones.

TRM cells may assume pathogenic roles if they become over-sensitized or autoreactivated. However, TRM cells are the first line protector of the immune system against the pathogen at the same time. Therefore, they play or stimulate to play an important role in effective treatment or vaccination. It was found that presence of CD8+ TRM cells is associated with good prognosis in various cancers.

**61**

**Author details**

Hasan Akbaba

Faculty of Pharmacy, Ege University, Izmir, Turkey

provided the original work is properly cited.

\*Address all correspondence to: hasan.akbaba@ege.edu.tr

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Resident Memory T Cells*

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

Unlike other T cell subsets, TRM cells are not present in the blood. This is one of the major logistical barriers to the study of TRM cells. Therefore, TRM studies in humans have been limited due to the need for biopsy. In human NLT tissues, TRM isolation should be performed in a small biopsy volume, they should be phenotypically redefined and distinctive surface markers should be identified for humans. However, TRM cell-mediated vaccination and effective T cell treatments against solid tumors can be achieved by overcoming these problems in the following years.

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

*Cells of the Immune System*

against solid tumors [73].

**7. Conclusion**

common ones.

tion of TRM against cancer are very promising.

and eliminate tumor cells [10, 73].

TRM-mediated vaccine development researches against infectious agents are not limited to PF HSV and HIV. Moreover, vaccine studies are being carried out in order to provide first step protection against many infectious agents such as influenza, varicella, Human papillomavirus (HPV), toxoplasma, etc. [8, 38, 43, 137, 138]. In the context of TRM cells, cancer should also be emphasized. Currently, developed cancer vaccines are generally aimed for the treatment and the number of prophylactic vaccines is relatively low. Therefore, vaccination studies for the forma-

Recent studies suggest that TRM cells also play a vital part in cancer surveillance [57, 139]. It was demonstrated in many studies that TRM cells generated by vaccines can protect against tumor challenge [10, 55, 140, 141]. Formation of CD8+ T cells is one of the main objectives in cancer vaccine development against solid tumors. The type of CD8+ T cells that can migrate and localize in tumor microenvironments are TRM cells. [55]. It was found that presence of CD8+ TRM cells is associated with good prognosis in various cancers [57]. TRM cells can act in three major ways

• TRM cells can express cytokines: TRM cells can produce cytokines such as perforin and granzyme B, and other effector molecules such as IFNγ and TNFα

• TRM cells may promote tumor-immune equilibrium: CD8+ TRM cells can contribute tumor immunosurveillance and they prevent tumor outgrowth

• TRM cells express inhibitory checkpoint molecules: TRM cells also predominantly express checkpoint receptors such as programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), and T-cell

It is becoming increasingly clear that TRM cells play an integral role in tumor surveillance in both animal models and human cancers. However, the role of TRM

The knowledge about TRM cells is at an early stage. Moreover, it has been revealed only in recent decades that TRM cells are unique subsets. It was found that TRM cells become resident by their phenotypic characteristics by adopting the microenvironment of the host tissue. TRM cells are transcriptionally, phenotypi-

TRM cells have different phenotypes show heterogeneity depending on the host tissue microenvironment. Requirement for TRM generation, proliferation, migration, and maintenance vary in different kind of tissues. In order to distinguish TRM cells from other T cell subsets, in most of the studies in both mice and humans, identification markers such as CD103, CD69, and Cd49a were the most

TRM cells may assume pathogenic roles if they become over-sensitized or autoreactivated. However, TRM cells are the first line protector of the immune system against the pathogen at the same time. Therefore, they play or stimulate to play an important role in effective treatment or vaccination. It was found that presence of

cally, and functionally distinct from other circulating T cell subsets.

CD8+ TRM cells is associated with good prognosis in various cancers.

immunoglobulin and mucin-domain containing-3 (Tim-3) [55, 80].

without completely eliminating cancerous cells [73, 142, 143].

cells in solid human cancers should be further investigated.

**60**

Unlike other T cell subsets, TRM cells are not present in the blood. This is one of the major logistical barriers to the study of TRM cells. Therefore, TRM studies in humans have been limited due to the need for biopsy. In human NLT tissues, TRM isolation should be performed in a small biopsy volume, they should be phenotypically redefined and distinctive surface markers should be identified for humans. However, TRM cell-mediated vaccination and effective T cell treatments against solid tumors can be achieved by overcoming these problems in the following years.
