Tissue-resident memory T cell explained

Tissue-resident memory T cells or T_RM cells represent a subset of a long-lived memory T cells that occupies epithelial, mucosal and other tissues (skin, mucosa, lung, brain, pancreas, gastrointestinal tract) without recirculating. T_RM cells are transcriptionally, phenotypically and functionally distinct from central memory (T_CM) and effector memory (T_EM) T cells which recirculate between blood, the T cell zones of secondary lymphoid organ, lymph and nonlymphoid tissues. Moreover, T_RM cells themself represent a diverse populations because of the specializations for the resident tissues. The main role of T_RM cells is to provide superior protection against infection in extralymphoid tissues.^{[1] [2]}

Phenotype

Three cell surface markers that has been associated with T_RM are CD69, CD49a, and CD103. CD69 suppresses response to the S1P chemoattractant from blood and lymph and prevents T_RM cells from exiting peripheral tissue.^{[3] [4]} CD49a mediates tissue residency directly and marks cells with the most effector-like capabilities including IFN-gamma production and the ability to directly kill infected cells.^{[5] [6]} CD103 is expressed by many CD8⁺ T_RM cells and rarely by CD4⁺ T_RM cells, usually in conjunction with CD49a.^[7] T_RM cells have tissue residency-promoting transcriptional signature with features specific to individual tissues and features necessary for long-term survival in these tissues.^[8]

• Skin T_RM: T_RM cells in the skin express cutaneous lymphocyte antigen (CLA) and CCR8 which are skin homing antigens. They have also higher expression of markers CD103 and CD69, integrins, cytokine/growth factor receptors and signaling molecules CD49a, CD122 and PD-1.^{[9] [10] [11]} On the other hand, they have downregulated chemokine receptors CCR7 and S1P1 which are important for recirculation. Skin T_RM cells can survive in the skin for years depending upon IL-15 and fatty acid metabolism.^{[12] [13] [11]} IL-15 and TGF-ß are required for differentiation of T_RM cells in the skin in mouse models.^{[14] [11]}
• Lung T_RM: Lung T_RM cells play important role in protection against respiratory infections. CD4⁺ follicular helper T_RM cells promotes protection against virus infection by inducing B cells and CD8⁺ T cells. CD8⁺ T_RM cells produce IFN-gamma which assists in viral clearance. T_RM cells can also recruit neutrophils in case of bacterial infection. However, pathologic inflammation caused by lung T_RM cells can lead to development of asthma or fibrosis. Human lung T_RM CD4⁺ CD103⁺ cells express higher levels of CD103, CTLA4, KLRC1 and ICOS. CTLA4 is an inhibitor protein which role may lie in limitation of excessive effector and cytolytic activity which could lead to immune pathologies.^[15] On the other hand, they have lower expression of S1P receptor S1PR1, homing receptor to lymph node CD62L, activation marker KLRG1, KLF2 and CCR7 than T_EM in the blood.^[16]
• Other T_RM: The majority of T_RM express CD69 and CD103 markers. However, T_RM without CD103 expression can be found in intestines, secondary lymphoid organs and liver. Moreover, T_RM without both markers, CD69 and CD103, were found in substantial proportion in pancreas, salivary glands and female reproductive tract of mice.^[17]

Development

T_RM cells develop from circulating effector memory T cell precursors in response to antigen. The main role in formation of T_RM cells has CD103 and expression of this integrin is dependent on the cytokine TGF-β. CD8⁺ effector T cells that lack TGF-β fail to upregulate CD103, and subsequently do not differentiate into T_RM cells. The important role in development of T_RM cells have various cytokines that support T_RM cell formation and survival. For example, homeostatic cytokine IL-15, pro-inflammatory cytokines such as IL-12 and IL-18, and barrier cytokines such as IL-33.^{[18] [19] [20]} Also, generation of CD103⁺ T_RM cells requires low expression of Eomes and T-bet transcription factors.^[16]

Shortly after antigen-specific response in the non-lymphoid tissue, infected tissue is occupied by CD8⁺ effector-stage T cells (T_EFF). These cells present early in the tissue have higher expression of some genes typical for T_RM and at the peak of the T cell response, local T cell population expresses more than 90% of the T_RM gene signature.^[21] This shows that differentiation process of T_RM cells starts early during immune response.^[8]

Function

T_RM cells reside in many tissues that create barriers against outside environment and thus provide defense against repeatedly incoming pathogens. In the skin, lung, brain, and vagina T_RM cells are required to provide immediate rapid control of re-infection. CD4⁺ T_RM cells provide better protection against repeated infection with influenza in comparison with circulating memory CD4⁺ T cells.^{[22] [23]} Moreover, CD8⁺ T_RM cells also play role in the protection against malignancies. T_RM cells express granzyme B which helps limit the spread of pathogens at the site of infection. Also, phenotypic and functional diversity is not only in T_RM from different tissues, but it could be found in various T_RM subsets within the same tissue. For example, CD49a distinguishes CD8⁺ T_RM subsets with different functions. T_RM cells positive for this marker produce perforin and IFNɤ. On the other side, T_RM without CD49a expression produce IL-17.^[24] IFNɤ production depends on the localization of T_RM in the tissue niche. CD8⁺ T_RM in mouse airways produce significant IFNɤ in comparison to parenchymal CD8⁺ T_RM cells.^[25] After reactivation, T_RM cells undergo rapid proliferation in situ. Increase in T_RM numbers after repeated exposure to antigens is not derived just from existing T_RM, but circulating T cells contribute to the generation and higher numbers of TRM, too. Also, not every T_RM express CD69 and CD103 what support phenotypic heterogeneity of T_RM cells. T_RM cells are able to activate innate and adaptive leukocytes to protect the host.^{[26] [2] [27] [28]} Cooperation of T_RM cells with other memory T cell populations provide tissue surveillance and clearance of the infections.^{[29] [30] [11]}

Potential of CD8⁺ T_RM cells in cancer immunotherapy

Cytotoxic CD8⁺ T lymphocytes are able to recognize malignant cells. Production of neoantigens by tumour cells can lead to peptides which are presented to CD8⁺ T cells bound to MHC I. After antigen recognition, CD8⁺ T cells destroy tumor cells using IFN-ɤ, TNF-α, granzyme B and perforin. However, malignant cells can avoid this elimination by various mechanisms such as the loss of MHC I molecule, induction of anti-inflammatory tumor micro-environment, inhibition of T cell function, upregulation of ligands whose interactions with CD8⁺ T cell receptors results in their suppression etc. Immune checkpoint therapy and tumor-infiltrating lymphocytes (TIL) therapy are cancer immunotherapy strategies whose principle lies in suppression of tumor cell inhibitory pathways or in introduction of expanded CD8⁺ T cells. Whereas large fraction of TILs are T_RM cells, they are candidates for solid cancer immunotherapy.

T_RM cells infiltrated in tumors have protective role and are associated with good clinical results in various cancer types, but not in pancreatic cancer. They have decreased expression of IFN-ɤ, TNF-α and IL-2 in comparison with circulating T cells in melanoma patients what suggest different mechanism for tumor growth control. Upregulation of granzyme A and granzyme B was found in T_RM cells in lung carcinoma patients. However, in T_RM cells are also upregulated immune checkpoint receptors. This suggests, that most of the tumor T_RM show an exhausted phenotype which may be saved by immune checkpoint inhibitor therapies. Nonidentical tumors may contain different T_RM populations.

Role in disease pathogenesis

Autoreactive T_RM cells and reduced ratio or activity of regulatory T cells (Tregs) which protects body from autoimmunity by securing self-tolerance may induce autoimmune diseases sucha as vitiligo, cutaneous lupus erythematosus, psoriasis, alopecia areata, cicatricial alopecia,multiple sclerosis, lupus nephritis, rheumatoid arthritis and autoimmune hepatitis.^{[11] [31]}

Vitiligo

Vitiligo is an autoimmune skin disease with white spots phenotype. CD8⁺ T lymphocytes destroy melanocytes in some parts of the skin what manifest like white spots on the skin. Multiple genes as well as environment play role in developing vitiligo and migration of CD8⁺ T cells correlates with the state of disease. 80% of autoreactive CD8⁺ T cells which are specific towards melanocyte self-antigens express CD69 or CD69 and CD103 T_RM markers. There is also higher number of CD49a⁺ CD8⁺ CD103⁺ T cells with cytotoxic potential in epiderma and derma of the vitiligo patients in comparison with healthy skin. Treatment of vitiligo lies in inhibition of JAK/STAT signaling pathway using JAK inhibitors. T_RM cells have reduced IFNɤ production and white spots on skin disappear. However, the treatment can not be stopped, because white spots will appear again.

Cutaneous Lupus Erythematosus (CLE)

CLE is another autoimmune skin disease with several subtypes. Common feature is interface dermatitis or inflammation at the dermal-epidermal junction. Again, contribution of genetic and environment factors lead to the development of CLE. It is not really clear what is the specificity of the T cell causing CLE in the skin, but some studies showed T cells reactive to nucleosomes/histones. Except aberrant T cell signaling which conduces to the pathogenesis of CLE, increased presence of T_RM was also found in the skin of CLE patients refractory to antimalarials. Treatment lies in JAK/STAT inhibitors, but can not be stopped, because skin lessions will appear again.

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