Tissue-resident memory T cell

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Tissue-resident memory T cells or TRM 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. TRM cells are transcriptionally, phenotypically and functionally distinct from central memory (TCM) and effector memory (TEM) T cells which recirculate between blood, the T cell zones of secondary lymphoid organ, lymph and nonlymphoid tissues. Moreover, TRM cells themself represent a diverse populations because of the specializations for the resident tissues. The main role of TRM cells is to provide superior protection against infection in extralymphoid tissues. [1] [2]

Contents

Phenotype

Three cell surface markers that has been associated with TRM are CD69, CD49a, and CD103. CD69 suppresses response to the S1P chemoattractant from blood and lymph and prevents TRM 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+ TRM cells and rarely by CD4+ TRM cells, usually in conjunction with CD49a. [7] TRM cells have tissue residency-promoting transcriptional signature with features specific to individual tissues and features necessary for long-term survival in these tissues. [8]

Development

TRM cells develop from circulating effector memory T cell precursors in response to antigen. The main role in formation of TRM 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 TRM cells. The important role in development of TRM cells have various cytokines that support TRM 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+ TRM 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 (TEFF). These cells present early in the tissue have higher expression of some genes typical for TRM and at the peak of the T cell response, local T cell population expresses more than 90% of the TRM gene signature. [21] This shows that differentiation process of TRM cells starts early during immune response. [8]

Function

TRM 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 TRM cells are required to provide immediate rapid control of re-infection. CD4+ TRM cells provide better protection against repeated infection with influenza in comparison with circulating memory CD4+ T cells. [22] [23] Moreover, CD8+ TRM cells also play role in the protection against malignancies. [4] TRM 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 TRM from different tissues, but it could be found in various TRM subsets within the same tissue. For example, CD49a distinguishes CD8+ TRM subsets with different functions. TRM cells positive for this marker produce perforin and IFNɤ. On the other side, TRM without CD49a expression produce IL-17. [24] IFNɤ production depends on the localization of TRM in the tissue niche. CD8+ TRM in mouse airways produce significant IFNɤ in comparison to parenchymal CD8+ TRM cells. [25] [15] After reactivation, TRM cells undergo rapid proliferation in situ. Increase in TRM numbers after repeated exposure to antigens is not derived just from existing TRM, but circulating T cells contribute to the generation and higher numbers of TRM, too. [15] Also, not every TRM express CD69 and CD103 what support phenotypic heterogeneity of TRM cells. [17] TRM cells are able to activate innate and adaptive leukocytes to protect the host. [26] [2] [27] [28] Cooperation of TRM cells with other memory T cell populations provide tissue surveillance and clearance of the infections. [29] [30] [11]

Potential of CD8+ TRM 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 TRM cells, they are candidates for solid cancer immunotherapy. [4]

TRM 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 TRM cells in lung carcinoma patients. However, in TRM cells are also upregulated immune checkpoint receptors. This suggests, that most of the tumor TRM show an exhausted phenotype which may be saved by immune checkpoint inhibitor therapies. Nonidentical tumors may contain different TRM populations. [4]

Role in disease pathogenesis

Autoreactive TRM 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 TRM 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. TRM cells have reduced IFNɤ production and white spots on skin disappear. However, the treatment can not be stopped, because white spots will appear again. [11]

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 TRM 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. [11]

Related Research Articles

<span class="mw-page-title-main">Autoimmunity</span> Immune response against an organisms own healthy cells

In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". Prominent examples include celiac disease, post-infectious IBS, diabetes mellitus type 1, Henoch–Schönlein purpura (HSP) sarcoidosis, systemic lupus erythematosus (SLE), Sjögren syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis (RA), ankylosing spondylitis, polymyositis (PM), dermatomyositis (DM), and multiple sclerosis (MS). Autoimmune diseases are very often treated with steroids.

<span class="mw-page-title-main">Dendritic cell</span> Accessory cell of the mammalian immune system

A dendritic cell (DC) is an antigen-presenting cell of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system. They act as messengers between the innate and adaptive immune systems.

<span class="mw-page-title-main">T cell</span> White blood cells of the immune system

T cells are one of the important types of white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface.

<span class="mw-page-title-main">T helper cell</span> Type of immune cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.

The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells. Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.

Cross-presentation is the ability of certain professional antigen-presenting cells (mostly dendritic cells) to take up, process and present extracellular antigens with MHC class I molecules to CD8 T cells (cytotoxic T cells). Cross-priming, the result of this process, describes the stimulation of naive cytotoxic CD8+ T cells into activated cytotoxic CD8+ T cells. This process is necessary for immunity against most tumors and against viruses that infect dendritic cells and sabotage their presentation of virus antigens. Cross presentation is also required for the induction of cytotoxic immunity by vaccination with protein antigens, for example, tumour vaccination.

Gut-associated lymphoid tissue (GALT) is a component of the mucosa-associated lymphoid tissue (MALT) which works in the immune system to protect the body from invasion in the gut.

Memory T cells are a subset of T lymphocytes that might have some of the same functions as memory B cells. Their lineage is unclear.

Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that would otherwise have the capacity to elicit an immune response in a given organism. It is induced by prior exposure to that specific antigen and contrasts with conventional immune-mediated elimination of foreign antigens. Tolerance is classified into central tolerance or peripheral tolerance depending on where the state is originally induced—in the thymus and bone marrow (central) or in other tissues and lymph nodes (peripheral). The mechanisms by which these forms of tolerance are established are distinct, but the resulting effect is similar.

<span class="mw-page-title-main">Intraepithelial lymphocyte</span>

Intraepithelial lymphocytes (IEL) are lymphocytes found in the epithelial layer of mammalian mucosal linings, such as the gastrointestinal (GI) tract and reproductive tract. However, unlike other T cells, IELs do not need priming. Upon encountering antigens, they immediately release cytokines and cause killing of infected target cells. In the GI tract, they are components of gut-associated lymphoid tissue (GALT).

In immunology, peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in the immune periphery. Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease. Peripheral tolerance prevents immune response to harmless food antigens and allergens, too.

<span class="mw-page-title-main">CD69</span>

CD69 is a human transmembrane C-Type lectin protein encoded by the CD69 gene. It is an early activation marker that is expressed in hematopoietic stem cells, T cells, and many other cell types in the immune system. It is also implicated in T cell differentiation as well as lymphocyte retention in lymphoid organs.

Gamma delta T cells are T cells that have a γδ T-cell receptor (TCR) on their surface. Most T cells are αβ T cells with TCR composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. In contrast, γδ T cells have a TCR that is made up of one γ (gamma) chain and one δ (delta) chain. This group of T cells is usually less common than αβ T cells, but are at their highest abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).

The following outline is provided as an overview of and topical guide to immunology:

T helper 3 cells (Th3) are a subset of T lymphocytes with immunoregulary and immunosuppressive functions, that can be induced by administration of foreign oral antigen. Th3 cells act mainly through the secretion of anti-inflammatory cytokine transforming growth factor beta (TGF-β). Th3 have been described both in mice and human as CD4+FOXP3− regulatory T cells. Th3 cells were first described in research focusing on oral tolerance in the experimental autoimmune encephalitis (EAE) mouse model and later described as CD4+CD25−FOXP3−LAP+ cells, that can be induced in the gut by oral antigen through T cell receptor (TCR) signalling.

Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage, ILCs contribute to immunity via the secretion of signalling molecules, and the regulation of both innate and adaptive immune cells. ILCs are primarily tissue resident cells, found in both lymphoid, and non- lymphoid tissues, and rarely in the blood. They are particularly abundant at mucosal surfaces, playing a key role in mucosal immunity and homeostasis. Characteristics allowing their differentiation from other immune cells include the regular lymphoid morphology, absence of rearranged antigen receptors found on T cells and B cells, and phenotypic markers usually present on myeloid or dendritic cells.

<span class="mw-page-title-main">Bronchus-associated lymphoid tissue</span>

Bronchus-associated lymphoid tissue (BALT) is a tertiary lymphoid structure. It is a part of mucosa-associated lymphoid tissue (MALT), and it consists of lymphoid follicles in the lungs and bronchus. BALT is an effective priming site of the mucosal and systemic immune responses.

Memory T cell inflation phenomenon is the formation and maintenance of a large population of specific CD8+ T cells in reaction to cytomegalovirus (CMV) infection.

Thomas S. Kupper is an American physician, academic, and clinician. His work with clinical and research experience spans dermatology, cutaneous oncology, and immunology. He is the Thomas B. Fitzpatrick Professor at Harvard Medical School, and chairs the Departments of Dermatology at Brigham and Women's Hospital. He also leads the Cutaneous Oncology Disease Center at the Dana Farber Cancer Institute.

Whole-cell vaccines are a type of vaccine that has been prepared in the laboratory in such a way to express immune cells such as cytokines, chemokines and other costimulatory molecules. When administered to the patients, these molecules will stimulate the immune system of the patient. The whole-cell vaccine simultaneously targets multiple antigens to activate the immune system and induces antigen-specific T-cell responses.

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