Immune system is a complex system which involves various organs, cells and molecules. As seen in the previous posts, the cellular components, or leucocytes are derived from the hemopoietic (hSC) stem cells. The hSC differentiates into the myeloid progenitor and the lymphoid progenitor cells. The myeloid progenitor can further differentiate into granulocytes (neutrophils, basophils, eosinophils and mast cells) or agranulocytes (monocytes, macrophages and dendritic cells). The lymphoid progenitor further differentiates into T cells, B cells or Natural Killer cells. In this post we shall concentrate on the T cells.
T cells are also known as T lymphocytes, as they occur in the lymphatic system. They are an essential part of the adaptive immune system and play very important role in the cell mediated immunity. T cells carry out immune surveillance by getting into bloodstream and circulating through tissues. These cells protect the body from pathogens and cancer cells and activates the immune cells to fight infection.
T cells have characteristic receptors for recognizing the antigens on their cell surface, known as T-cell receptor on their cell membrane, which helps in recognizing variety of antigens as peptides bound to major histocompatibility complex (MHC) molecules.
The morphology of T cell varies from spherical to elongated and flattened. The T cells get elongated when in motion during scanning or movement towards APCs, whereas they are elongated and flattened when immobile and in stable contact with the APC. Hence their shape varies as per their state of action.
T lymphocytes develop from haematopoietic stem cells (hSCs) in bone marrow. These hSC differentiate into lymphoid progenitor cells, which later differentiate into T cells.
The immature T cells from the bone marrow, then migrate to the thymus via the blood. The thymus is a lymphatic system gland whose main function is the development of mature T cells. In fact, the T in the name of T lymphocyte or T cell stands for the ‘thymus’, the site of its maturation.
Within the thymus, the T cells undergoes V(D)J recombination for the formation of an appropriate TCR, positive selection and negative selection. After these processes the T cell can not only recognize the antigens but also differentiate the self and non-self-antigens.
T cells are activated by signals from antigens they encounter. The antigens are presented to the T cells in form of peptides loaded onto the MHC molecules by the antigen presentating cells via its T-cell receptor. Once the T-cell receptor binds to the MHC molecule, the antigen-presenting cell secretes cell signalling proteins called cytokines. Cytokines activates the T cells and signal the T cell to destroy the specific antigen. The activated T cell multiplies and differentiates into helper T cells. Helper T cells initiate the production of cytotoxic T cells, B cells, macrophages, and other immune cells to terminate the antigen.
Types and function:
Depending on the signals and environment, the T cells differentiate into any one of the effector cell types, each having specific functions in the immune response. Different type of effector T cells and their functions are as follows:
- 1. Cytotoxic T lymphocytes (CTL):
These cells are also called CD8+ T cells as their TCR is accompanied with the CD8 glycoprotein, which helps the TCR to recognise the MHC I molecule specifically and activate CTL cells. As we know the MHC I molecule is present on all the cells of the body. Hence, these cells are involved in the direct destruction of damaged self-cells, which includes cancerous and pathogen- (bacteria or virus) infected cells.
(Just for info: Watch this interesting video on how the killer T cells kills a cancer cell)
Cytotoxic T cells can induce target cells to undergo programmed cell death or apoptosis. These cells contain granules which are modified lysosomes containing proteins, which can lead the target cell to undergo apoptosis. The main proteins in these granules are perforin, (forms pores cell membranes of target damaged cells) and granzymes (serine proteases).
Another perforin-independent mechanism of cytotoxicity of CTL involves the binding of Fas (on target cells) and the Fas ligand (on activated CTL surface). This interaction leads to activation of caspases, which induce apoptosis in the target cell. Cytotoxic T cells also release cytokines like IFN-γ, TNF-α and TNF-β, which help fight various infections.
CTL plays a major role in transplant organ rejection which is identified as infected cells and attacked.
(Just for info: Read this paper to know more about the ‘Mechanism of cellular rejection in transplantation’.)
- 2. Helper T cells
The helper T cells are also called CD4+ T cells as they have a membrane glycoprotein CD4, which acts as a co-receptor with TCR and helps specifically recognise MHC II molecule. The MHC II molecules are present on only the antigen presenting cells.
The Th cells co-ordinate cells of both the innate and the adaptive immune system and play important role in various events like activation of cytotoxic T cells and macrophages, maturation of B cells into plasma cells and memory B cells, antibody production by B cells, recruitment of PMNs, eosinophils and basophils to the site of infection/inflammation, increase in microbiocidal activity of macrophages, development of tolerance and suppression of inflammatory responses.
The CD4+ helper T cells are a heterogenous group of cells, and have several subsets which includes: Th1, Th2, Th17, T follicular helper (Tfh) cells and regulatory CD4+ T cells (Tregs):
2.i. Th1 Cells:
Th1 cells are involved with the elimination of intracellular pathogens. Th1 cells are induced by antigen-presenting cells that retain microbes in intracellular vesicles. Such antigens cannot be attacked by the CTL. Th1 cells predominantly secrete IFNγ, lymphotoxin α (Lfα), and IL2. IFNγ plays major role in the activation of mononuclear phagocytes (like macrophages, microglial cells) and improves their phagocytic activity. Hence enhance cell-mediated immune responses as well.
2.ii. Th2 Cells:
Th2 cells mount immune response to large extracellular parasites (like helminthes) and induce allergic diseases like asthma. The main cytokines secreted by them are IL4, IL5, IL9, IL13, IL10, IL25 and amphiregulin. These cells are required for humoral immunity and are also involved in allergic reactions.
(Just for info: Read this paper about the various cytokines, their receptors, function and role in Diseases.)
2.iii. Th17 Cells:
These cells are specialized in the production of interleukin-17 (IL-17), which is highly inflammatory cytokine. They offer protection against invaders that Th1 or Th2 cells are not able to deal with like extracellular bacteria and some fungi.
Th17 cells play an important role in various inflammatory immune-mediated diseases such as rheumatoid arthritis, multiple sclerosis, psoriasis and asthma. It is also involved in the many cases of tumorigenesis and transplant rejection.
(Just for info: Read this paper titled ‘Significance of Th17 Immunity in Transplantation.’)
2.iv. T follicular helper (Tfh) cells:
Follicular helper T (Tfh) cells are specialized T cells involved in the development of the B cells in the germinal center (GC). GC sites are located in secondary lymphoid organs (like tonsil, spleen and lymph nodes) where B cells undergo rapid proliferation and antibody diversification and differentiate into antibody secreting plasma cells and memory B cells.
These cells provide B cell help in processes like somatic hypermutation, and class switching to generate long-lasting humoral immunity.
(Just for info: Want to know more about Tfh cells? Read this paper.)
2.v. Regulatory T cells:
The regulatory T cells (Tregs) are CD4 + cells. These cells are also called as suppressor T cells as they can suppress the response of B cells and other T cells to the antigens. The suppression of immune cells is required after the immune system gets rid of the antigens/pathogens and is no longer required. Hence, these cells play a very important role in homeostasis.
Any defect in the functioning of these cells leads to the development of an autoimmune disease and immune cells start attacking individual’s own tissue.
(Just for info: Read about the therapeutic potential of enhancing Treg cells in patients with inflammatory disorders.)
- 3. Natural Killer T (NKT) cells
Natural Killer T (NKT) cells are an rare subset of T cells and are less than 1% in peripheral blood of humans and other primates. NKT cells are part of innate immune system and act very rapidly. These cells recognize antigen presented by the nonpolymorphic MHC class I-like CD1d molecules and are characterized by a restricted TCR repertoire due to the presence of an invariant TCR alpha chain paired with a limited number of TCR beta chains.
NKT cells have features of both T cells and natural killer cells. These cells have TCR as well as several surface cell markers present on the natural killer cells. These cells can detect infected or cancerous self-cells and attack them.
Low numbers of NKT cells are found in all the locations where T and NK cells are found, like peripheral blood, thymus, bone marrow, spleen, liver, and lymph nodes. When activated they secrete cytokine first and then differentiate into effector cells. Due to this rapid action, they are important part of innate response against bacterial and viral infections.
These cells are strongly immunoregulatory as they secrete several cytokines. Some of the cytokines secreted by NKT cells leads to activation of CTL cells and Th cells hence linking innate and adaptive immune responses for stronger action against the invader.
(Just for info: Read this paper titled ‘Novel Approaches to Exploiting Invariant NKT Cells in Cancer Immunotherapy’)
- 4. Memory T cells:
The different subsets of T cells act to eliminate the pathogen from the body. Once the pathogen is eliminated, most effector cells die, but a small subset of long-lived memory cells continue to survive. These memory cells can respond rapidly in case of reinfection by the same antigen/pathogen.
Helper T cells and cytotoxic T cells can become memory T cells. These subtypes of T cells are stored in the lymph nodes and spleen and provide lifetime protection against a antigen once encountered.
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Have a nice day!
Read other posts by The Biotech Notes:
Chaplin (2010). Overview of the Immune Response. The Journal of allergy and clinical immunology. 125 (2 Suppl): S3-23.
Crotty (2014) T follicular helper cell differentiation, function, and roles in disease. Immunity. 2014 Oct 16; 41(4): 529–542.
Luckheeram et al. (2012) CD4+T Cells: Differentiation and Functions. Clinical & developmental immunology. 2012 (925135).
Chap 11:NK, γδ T and NKT Cells (2014) Primer to the Immune Response (2nd Ed).
Rout & Kaur (2014) Cellular Immune Responses in Natural and Non-natural Hosts of Simian Immunodeficiency Virus Infection. Natural Hosts of SIV: 197-215.
Linterman & Vinuesa (2010) Development of T Cell Immunity. Progress. Molecular Biology and Translational Science. 92: 1-326.
Pahl &Vaziri (2015) Chap 24: Immune Function in Chronic Kidney Disease. Chronic Renal Disease :285-297.
Lin et al (2015) Morphological change of CD4+ T cell during contact with DC modulates T-cell activation by accumulation of F-actin in the immunology synapse. BMC Immunol. 16: 49.
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Wolf et al. (2018) Novel Approaches to Exploiting Invariant NKT Cells in Cancer Immunotherapy. Front Immunol. 9:384.