T Cell (T Lymphocyte)- Definition, Types, Development, Applications

T cells are a type of white blood cell that is an essential part of the immune system . They are one of two primary types of lymphocytes, the other being B cells, that determine the specificity of immune response to antigens (foreign substances) in the body. T cells originate in the bone marrow and mature in the thymus . They play a central role in the adaptive immune response and can be distinguished from other lymphocytes by the presence of a T-cell receptor on their cell surface . T cells are important for cell-mediated immunity and the activation of immune cells to fight infection.

There are different types of T cells that perform different functions in the immune system. These include:

• Helper T cells (CD4+ T cells): These are lymphocytes that assist the maturation of other lymphocytes like B cells to differentiate into plasma cells and memory B cells. They also secrete cytokines that regulate the overall immune response.
• Cytotoxic T cells (CD8+ T cells): These are lymphocytes that destroy virus-infected cells or tumor cells as well as cells involved in transplants. They recognize their target cells by binding to short peptides present together with class I MHC molecules.
• Memory T cells: These are long-lived lymphocytes that can quickly expand into a large number of effector T cells when re-exposed to the antigen that activated them in the first place. They provide long-term immunity against specific pathogens.
• Regulatory T cells: These are lymphocytes that control immune reactions and prevent autoimmune diseases. They suppress autoreactive T cells that escape the negative selection process in the thymus.

The development and maturation of T cells involve a complex process of gene rearrangement, selection, activation and differentiation. The process begins with hematopoietic stem cells in the bone marrow that differentiate into common lymphoid progenitors. A subset of these progenitors migrates to the thymus, where they become engrafted and undergo further differentiation into various types of T cells. The thymus provides a specialized microenvironment that supports the development of T cells and ensures their self-tolerance and diversity .

T cells are crucial for the protection of the body against various pathogens and harmful cells. They can also be used for immunological treatments for cancer, such as chimeric antigen receptor (CAR) T cell therapy. This involves engineering T cells to express receptors that can recognize specific antigens on malignant cells and kill them.

T cells are a type of white blood cell that belongs to the lymphocyte family. Lymphocytes are one of the main components of the adaptive immune system, which is responsible for generating specific and long-lasting responses to foreign invaders and harmful cells. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface. The TCR is a protein complex that can recognize and bind to specific antigens (molecules that trigger an immune response) presented by other cells.

T cells are named after the thymus, which is a gland located behind the sternum where T cells develop and mature. The thymus provides a specialized microenvironment for T cells to undergo gene rearrangements, selection processes, and differentiation into various subtypes.

T cells play a central role in the adaptive immune system by regulating and executing different functions depending on their subtype. Some T cells help activate other immune cells, such as B cells and macrophages, while others directly kill infected or abnormal cells. T cells can also suppress or modulate immune responses to prevent excessive inflammation or autoimmunity.

T cells are produced in the bone marrow from hematopoietic stem cells, which are the common precursors of all blood cells. T cells then migrate to the thymus, where they undergo several stages of development and maturation before entering the bloodstream and lymphatic system. T cells circulate in these fluids until they encounter their specific antigens on antigen-presenting cells (APCs), such as dendritic cells, macrophages, or B cells. Upon activation by APCs, T cells proliferate and differentiate into effector or memory T cells. Effector T cells perform various functions to eliminate the antigen, while memory T cells persist in the body and provide long-term immunity.

T cells are essential for protecting the body from infections, cancers, and autoimmune diseases. However, T cells can also cause damage to healthy tissues if they are not properly regulated or if they recognize self-antigens as foreign. Therefore, T cell development and activation are tightly controlled by various mechanisms to ensure a balanced and effective immune response.

T cells can be grouped into different categories based on their function, gene expression, and surface receptors. The main types of T cells are:

• Helper T cells (CD4+ T cells): These are the T cells that assist other immune cells, such as B cells, cytotoxic T cells, and macrophages, in fighting infections and diseases. They are called CD4+ T cells because they have a CD4 receptor on their surface that binds to class II MHC molecules on antigen-presenting cells (APCs). Helper T cells secrete various cytokines that regulate the immune response and activate other effector cells. Helper T cells can be further divided into subtypes based on the cytokines they produce and the toll-like receptors they express. Some of these subtypes are:

  • Th1 cells: These are the helper T cells that promote cell-mediated immunity by stimulating macrophages and cytotoxic T cells to destroy intracellular pathogens, such as viruses and bacteria. They produce cytokines like interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) that enhance the phagocytic and cytotoxic activity of other immune cells. Th1 cells are also involved in autoimmune diseases, such as type 1 diabetes and multiple sclerosis, where they attack the body`s own tissues.
  • Th2 cells: These are the helper T cells that promote humoral immunity by stimulating B cells to produce antibodies against extracellular pathogens, such as parasites and allergens. They produce cytokines like interleukin-4 (IL-4) and interleukin-13 (IL-13) that induce B cell differentiation and class switching. Th2 cells are also involved in allergic diseases, such as asthma and eczema, where they trigger an excessive antibody response that causes inflammation and tissue damage.
  • Th17 cells: These are the helper T cells that protect against fungal and bacterial infections by recruiting neutrophils and monocytes to the site of infection. They produce cytokines like interleukin-17 (IL-17) and interleukin-22 (IL-22) that induce the production of antimicrobial peptides and inflammatory mediators by epithelial cells and fibroblasts. Th17 cells are also involved in chronic inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease, where they cause tissue destruction and fibrosis.
  • Treg cells: These are the regulatory T cells that suppress the immune response and maintain self-tolerance by preventing autoimmunity and excessive inflammation. They express a transcription factor called forkhead box P3 (FOXP3) that is essential for their development and function. They also express CD25, which is a subunit of the interleukin-2 (IL-2) receptor, that allows them to consume IL-2 and deprive other T cells of this growth factor. Treg cells can inhibit other T cells by direct cell-cell contact or by secreting anti-inflammatory cytokines like interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β).

• Cytotoxic T cells (CD8+ T cells): These are the T cells that directly kill infected or abnormal cells, such as virus-infected cells, tumor cells, or transplant cells. They are called CD8+ T cells because they have a CD8 receptor on their surface that binds to class I MHC molecules on target cells. Cytotoxic T cells recognize short peptides derived from intracellular antigens that are presented by class I MHC molecules on APCs or target cells. Cytotoxic T cells use two main mechanisms to induce cell death:

  • Perforin-granzyme pathway: This is the mechanism where cytotoxic T cells release perforin molecules that form pores on the target cell membrane, allowing granzymes to enter the cell and activate caspases that trigger apoptosis.
  • Fas-FasL pathway: This is the mechanism where cytotoxic T cells express Fas ligand (FasL) on their surface that binds to Fas receptor on the target cell membrane, inducing a signaling cascade that leads to apoptosis.

Cytotoxic T cells also secrete cytokines like IL-2 and IFN-γ that stimulate their own proliferation and differentiation, as well as enhance the activity of other immune cells.

• Memory T cells: These are the long-lived T cells that persist after an infection or vaccination and provide a rapid and enhanced response upon re-exposure to the same antigen. Memory T cells can express either CD4+ or CD8+ receptors, but they usually have a different phenotype than naïve or effector T cells. Memory T cells can be classified into subtypes based on their location, function, and gene expression. Some of these subtypes are:

  • Central memory T cells (T CM): These are the memory T cells that reside in secondary lymphoid organs, such as lymph nodes and spleen, where they can encounter antigens presented by APCs. They express high levels of CD62L and CCR7, which allow them to migrate to these organs via blood vessels. They also express high levels of CD44 and low levels of CD45RA, which indicate their activation status. They have a high proliferative potential and can differentiate into effector T cells upon antigen stimulation.
  • Effector memory T cells (T EM): These are the memory T cells that circulate in peripheral blood and tissues, where they can provide immediate protection against pathogens. They express low levels of CD62L and CCR7, which prevent them from entering secondary lymphoid organs. They also express high levels of CD45RO and low levels of CD27, which indicate their differentiation status. They have a low proliferative potential but can exert effector functions like cytokine production and cytotoxicity upon antigen recognition.
  • Tissue-resident memory T cells (T RM): These are the memory T cells that reside permanently in non-lymphoid tissues, such as skin, mucosa, brain, liver, lung, etc., where they can respond locally to pathogens or tissue damage. They express high levels of CD69 and CD103, which enable them to adhere to epithelial or endothelial cells in these tissues. They also express tissue-specific chemokine receptors that allow them to migrate within these tissues. They have a limited proliferative potential but can secrete cytokines and chemokines that recruit other immune cells to the site of infection or injury.
  • Virtual memory T cells (T VM): These are a subset of memory-like CD8+ T cells that do not originate from antigen-specific clonal expansion but rather from homeostatic proliferation in response to IL-15 or IL-7 signals. They express intermediate levels of CD44 and low levels of CD62L and CCR7. They have a broad repertoire of TCRs that can recognize various antigens with low affinity. They have a high proliferative potential but low effector functions compared to conventional memory T EM or memory-like effector CD8+T-cells.

T cells, like all other blood cells, originate from hematopoietic stem cells (HSCs) present in the bone marrow. In some cases, the development might begin in the fetal liver during embryonic development. The HSCs then develop into multipotent progenitors (MPPs) that retain the ability to differentiate into myeloid and lymphoid cells. Further differentiation leads to the formation of a common lymphoid progenitor (CLP) that can differentiate into T, B, or NK cells.

In the case of T cells, the CLPs move to the thymus via blood, where they become engrafted. The cells that reach the thymus are called double-negative (DN) cells as they do not express any of the CD4 or CD8 co-receptors. The DN cells can be further classified into four different stages (DN1 to DN4) based on their expression of CD44, CD25, and CD117 markers.

The thymus consists of four major compartments: the subcapsular zone, the cortex, the medulla, and the corticomedullary junction. The development of the thymocytes progresses through different stages in different regions of the thymus and can be traced by the alterations in the cell-surface marker expression and gene rearrangement.

The DN1 cells are early thymic progenitors (ETPs) that exhibit high levels of CD117 and account for about 0.01% of the total thymic T cell pool. The DN1 cells move from the corticomedullary junction into the deeper cortex towards the subcapsular region. Here, the cells differentiate into DN2 thymocytes, which include CD24+, CD25+, CD44+, and CD117+ cells. The DN2 thymocytes then experience a rearrangement of genes and the secretion of cytokines like IL-7.

The cells further differentiate into the DN3 stage, where the T cells express an invariant α-chain called pre-Tα. The rearrangement of genes together with the invariant chain produces signals to proceed with the process of T cell maturation. At the DN3 stage, the cells mature into DN4, which is further upregulated into CD4 and CD8 cells achieving a double positive (DP) status in the maturation process. The specificity and binding strength of the αβ T cell receptor determine the survival and differentiation of the cells.

The process is followed by two distinct processes: positive selection and negative selection.

Positive Selection

Positive selection is the process of movement of DP T cells to the cortex, where they encounter self-antigens presented by class I or class II MHC molecules on thymic cortical epithelial cells. The T cells that interact with moderate affinity with either class I or class II MHC molecules receive survival signals whereas others with low or high affinity undergo apoptosis. A large portion of the developing thymocytes die during this process, which lasts for a number of days.

In positive selection, the CD4+ cells interact well with class II MHC molecules whereas the CD8+ cells interact well with class I MHC molecules. This results in downregulation of one co-receptor and upregulation of another, leading to single positive (SP) T cells that express either CD4 or CD8.

Negative Selection

The SP T cells that survive positive selection move into the medulla and undergo negative selection which eliminates thymocytes with high affinity for self-antigens presented by class I or class II MHC molecules on medullary epithelial cells or dendritic cells. The T cells that interact too strongly with self-antigens receive apoptotic signals resulting in cell death. This process ensures self-tolerance and prevents autoimmune reactions.

During negative selection, however, some T cells are selected to form regulatory T (Treg) cells that express both CD4 and FOXP3 markers. These Treg cells are involved in suppressing autoreactive T cells that escape negative selection and maintaining immune homeostasis.

The SP T cells that successfully complete negative selection exit the thymus as mature naïve T cells that express either CD4+ or CD8+ co-receptors and a unique T cell receptor. These T cells then circulate in the blood and lymphatic system until they encounter their specific antigens on antigen-presenting cells.

T cells have various applications in immunology, biotechnology and medicine, as they are essential for the adaptive immune system and can be manipulated to target specific antigens. Some of the applications of T cells are:

• T cell antigen discovery: This is the process of identifying the peptide antigens that are recognized by T cell receptors (TCRs) on different types of T cells. This can help understand the antigenic landscape of the immune system and reveal novel targets for immunotherapy and vaccine development.
• T cell engineering: This is the process of modifying the TCRs or other molecules on T cells to enhance their specificity, affinity, function or persistence. This can be done by using genetic engineering, gene editing or synthetic biology techniques.
• T cell therapy: This is the process of using T cells as therapeutic agents to treat diseases such as cancer, infection or autoimmunity. This can be done by using autologous (from the same individual) or allogeneic (from a different individual) T cells that are either isolated from peripheral blood or generated in vitro.
  • Chimeric antigen receptor (CAR) T cell therapy: This is a type of T cell therapy that uses T cells that are engineered to express a synthetic receptor that can recognize a specific antigen on tumor cells or infected cells. The CAR consists of an extracellular antigen-binding domain (usually derived from an antibody) and an intracellular signaling domain (usually derived from CD3 and co-stimulatory molecules). CAR T cells can bypass the need for MHC presentation and can directly kill their target cells .
  • T cell receptor (TCR) therapy: This is a type of T cell therapy that uses T cells that are engineered to express a natural or modified TCR that can recognize a specific peptide-MHC complex on tumor cells or infected cells. TCR therapy can target intracellular antigens that are not accessible by antibodies or CARs, but requires matching of the MHC alleles between the donor and the recipient .
  • Tumor-infiltrating lymphocyte (TIL) therapy: This is a type of T cell therapy that uses T cells that are isolated from tumor tissues and expanded in vitro. TILs are enriched for tumor-specific T cells that can recognize a variety of antigens on tumor cells. TIL therapy requires surgical removal of tumor tissue and ex vivo manipulation of T cells .

• T cell vaccination: This is the process of using T cells as vaccines to induce protective immunity against pathogens or tumors. This can be done by using live attenuated (weakened) or killed (inactivated) T cells that express specific antigens or by using synthetic peptides or DNA that encode specific antigens.
  
  

T cells are a vital component of the adaptive immune system that can recognize and eliminate a wide range of pathogens and abnormal cells. T cells develop in the thymus and undergo a series of selection processes to ensure their specificity and tolerance. T cells can be classified into different types based on their function, co-receptor expression and cytokine production. T cells can also form memory cells that provide long-lasting protection against reinfection. T cells have various applications in immunotherapy, especially for cancer treatment. By engineering T cells to express chimeric antigen receptors (CARs), researchers can enhance their ability to target and kill tumor cells. T cell antigen discovery is an active area of research that aims to identify the antigens recognized by T cells in different diseases and conditions. Understanding the antigenic landscape of T cells can help design better vaccines and immunotherapies.

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