T cells belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. A lymphocyte is a type of White blood cell in the Vertebrate Immune system. Cell-mediated immunity is an Immune response that does not involve Antibodies or complement but rather involves the activation of Macrophages They can be distinguished from other lymphocyte types, such as B cells and natural killer cells by the presence of a special receptor on their cell surface called the T cell receptor (TCR). B cells are Lymphocytes that play a large role in the humoral immune response (as opposed to the cell-mediated immune response, which is governed by Natural killer cells (or NK cells) are a type of Cytotoxic Lymphocyte that constitute a major component of the Innate immune system. The T cell receptor or TCR is a molecule found on the surface of T lymphocytes (or T cells that is in general responsible for recognizing Antigens bound The abbreviation T, in T cell, stands for thymus, since it is the principal organ in the T cell's development. In Human anatomy, the thymus is an organ located in the upper Anterior portion of the chest cavity just behind the Sternum.

T cell subsets

Molecular association of CD8+ T cells with MHC class I and CD4+ T cells with MHC class II

Several different subsets of T cells have been described, each with a distinct function.

• Helper T cells (effector T cells or T_h cells) are the "middlemen" of the adaptive immune system. T helper cells (also known as effector T cells or Th cells) are a sub-group of Lymphocytes (a type of White blood cell or Immune system|Passive immunity|Innate immune system The adaptive immune system is composed of highly specialized systemic cells and processes that eliminate or prevent Pathogenic Once activated, they divide rapidly and secrete small proteins called cytokines that regulate or "help" the immune response. Cytokines are a category of signalling Proteins and Glycoproteins that like Hormones and Neurotransmitters, are used extensively in cellular Depending on the cytokine signals received, these cells differentiate into T_H1, T_H2, T_H17, or one of other subsets, which secrete different cytokines. T helper cells (also known as effector T cells or Th cells) are a sub-group of Lymphocytes (a type of White blood cell or T helper cells (also known as effector T cells or Th cells) are a sub-group of Lymphocytes (a type of White blood cell or T helper 17 cells ( Th17) are a subset of T helper cells producing Interleukin 17. CD4+ cells associated with MHC class II. MHC ( Major histocompatibility complex) Class II molecules are found only on a few specialized cell types including Macrophages Dendritic cells and

• Cytotoxic T cells (T_C cells, or CTLs) destroy virally infected cells and tumor cells, and are also implicated in transplant rejection. A cytotoxic T cell (also known as TC, CTL T-Killer cell cytolytic T cell CD8+ T-cells or killer T cell) belongs to a sub-group of T lymphocytes These cells are also known as CD8⁺ T cells (associated with MHC class I), since they express the CD8 glycoprotein at their surface. CD8 ( Cluster of differentiation 8 is a transmembrane Glycoprotein that serves as a Co-receptor for the T cell receptor (TCR Through SLOB interaction with helper T cells, these cells can be transformed into regulatory T cells, which prevent autoimmune diseases such as experimental autoimmune encephalomyelitis. T helper cells (also known as effector T cells or Th cells) are a sub-group of Lymphocytes (a type of White blood cell or Regulatory T cells (sometimes known as suppressor T cells) are a specialized subpopulation of T cells that act to suppress activation of the Immune system Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which results in an immune response against its own cells and tissues Experimental autoimmune encephalomyelitis, sometimes Experimental Allergic Encephalomyelitis ( EAE) is an animal model of Brain Inflammation. ^[1]

• Memory T cells are a subset of antigen-specific T cells that persist long-term after an infection has resolved. Memory T cells are a specific type of Infection -fighting T cell (also known as a T lymphocyte) that can recognize foreign invaders such as Bacteria An antigen (from antibody-generating) or immunogen is a substance that prompts the generation of Antibodies and can cause an immune response They quickly expand to large numbers of effector T cells upon re-exposure to their cognate antigen, thus providing the immune system with "memory" against past infections. Memory T cells comprise two subtypes: central memory T cells (T_CM cells) and effector memory T cells (T_EM cells). Memory cells may be either CD4+ or CD8+.

• Regulatory T cells (T_reg cells), formerly known as suppressor T cells, are crucial for the maintenance of immunological tolerance. Regulatory T cells (sometimes known as suppressor T cells) are a specialized subpopulation of T cells that act to suppress activation of the Immune system Immune or immunological tolerance is the process by which the Immune system does not attack an Antigen. Their major role is to shut down T cell-mediated immunity toward the end of an immune reaction and to suppress auto-reactive T cells that escaped the process of negative selection in the thymus. Two major classes of CD4+ regulatory T cells have been described, including the naturally occurring T_reg cells and the adaptive T_reg cells. Naturally occurring T_reg cells (also known as CD4⁺CD25⁺FoxP3⁺ T_reg cells) arise in the thymus, whereas the adaptive T_reg cells (also known as Tr1 cells or Th3 cells) may originate during a normal immune response. In Human anatomy, the thymus is an organ located in the upper Anterior portion of the chest cavity just behind the Sternum. Naturally occurring T_reg cells can be distinguished from other T cells by the presence of an intracellular molecule called FoxP3. FOXP3 ( Forkhead box P3 is a Gene involved in Immune system responses Mutations of the FOXP3 gene can prevent regulatory T cell development, causing the fatal autoimmune disease IPEX. Autoimmune diseases arise from an overactive Immune response of the body against substances and tissues normally present in the body

• Natural killer T cells (NKT cells) are a special kind of lymphocyte that bridges the adaptive immune system with the innate immune system. Natural killer T (NKT cells are a heterogeneous group of T cells that share properties of both T cells and natural killer (NK cells. Immune system|Passive immunity|Innate immune system The adaptive immune system is composed of highly specialized systemic cells and processes that eliminate or prevent Pathogenic Immune system|Adaptive immune systemThe innate immune system comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner Unlike conventional T cells that recognize peptide antigen presented by major histocompatibility complex (MHC) molecules, NKT cells recognize glycolipid antigen presented by a molecule called CD1d. The major histocompatibility complex ( MHC) is a large genomic region or Gene family found in most Vertebrates It is the most gene-dense region Once activated, these cells can perform functions ascribed to both T_h and T_c cells (i. e. , cytokine production and release of cytolytic/cell killing molecules).

• γδ T cells represent a small subset of T cells that possess a distinct TCR on their surface. The T cell receptor or TCR is a molecule found on the surface of T lymphocytes (or T cells that is in general responsible for recognizing Antigens bound A majority of T cells have a TCR composed of two glycoprotein chains called α- and β- TCR chains. The T cell receptor or TCR is a molecule found on the surface of T lymphocytes (or T cells that is in general responsible for recognizing Antigens bound Not to be confused with Peptidoglycan. Glycoproteins are proteins that contain Oligosaccharide chains ( Glycans) covalently attached However, in γδ T cells, the TCR is made up of one γ-chain and one δ-chain. This group of T cells is much less common (5% of total T cells) than the αβ T cells, but are found at their highest abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs). The mucous membranes (or mucosae; singular mucosa) are linings of mostly endodermal origin covered in Epithelium, which are involved in Intraepithelial lymphocytes (IEL are Lymphocytes found in the epithelial layer of mammalian mucosal linings such as the gastrointestinal (GI tract The antigenic molecules that activate γδ T cells are still widely unknown. However, γδ T cells are not MHC restricted and seem to be able to recognise whole proteins rather than requiring peptides to be presented by MHC molecules on antigen presenting cells. Some recognize MHC class IB molecules though. Human Vγ9/Vδ2 T cells, which constitute the major γδ T cell population in peripheral blood, are unique in that they specifically and rapidly respond to a small non-peptidic microbial metabolite, HMB-PP, an isopentenyl pyrophosphate precursor. Isopentenyl pyrophosphate (IPP is an intermediate in the classical HMG-CoA reductase pathway used by organisms in the biosynthesis of Terpenes and Terpenoids

T cell development in the thymus

See Thymocyte for in-depth review of thymic selection

All T cells originate from hematopoietic stem cells in the bone marrow. Thymocytes are T cell precursors which develop in the Thymus. Hematopoietic stem cells (HSCs are Stem cells that give rise to all the blood cell types including Myeloid ( Monocytes and Macrophages, Neutrophils Bone marrow is the flexible tissue found in the hollow interior of Bones In adults marrow in large bones produces new Blood cells It constitutes 4% of Hematopoietic progenitors derived from hematopoietic stem cells populate the thymus and expand by cell division to generate a large population of immature thymocytes. Hematopoietic stem cells (HSCs are Stem cells that give rise to all the blood cell types including Myeloid ( Monocytes and Macrophages, Neutrophils In Human anatomy, the thymus is an organ located in the upper Anterior portion of the chest cavity just behind the Sternum. Thymocytes are T cell precursors which develop in the Thymus. ^[2] The earliest thymocytes express neither CD4 nor CD8, and are therefore classed as double-negative (CD4^-CD8^-) cells. Thymocytes are T cell precursors which develop in the Thymus. As they progress through their development they become double-positive thymocytes (CD4⁺CD8⁺), and finally mature to single-positive (CD4⁺CD8^- or CD4^-CD8⁺) thymocytes that are then released from the thymus to peripheral tissues. In Human anatomy, the thymus is an organ located in the upper Anterior portion of the chest cavity just behind the Sternum.

About 98% of thymocytes die during the development processes in the thymus by failing either positive selection or negative selection, whereas the other 2% survive and leave the thymus to become mature immunocompetent T cells. Thymocytes are T cell precursors which develop in the Thymus.

Positive selection

Positive selection selects for T-cells capable of interacting with MHC.

Double-positive thymocytes move deep into the thymic cortex where they are presented with self-antigens (i. Thymocytes are T cell precursors which develop in the Thymus. In Anatomy and Zoology the cortex ( Latin: "bark" "rind" "shell" or "husk" is the outermost (or "superficial" An antigen (from antibody-generating) or immunogen is a substance that prompts the generation of Antibodies and can cause an immune response e. , antigens that are derived from molecules belonging to the host of the T cell) complexed with MHC molecules on the surface of cortical epithelial cells. The major histocompatibility complex ( MHC) is a large genomic region or Gene family found in most Vertebrates It is the most gene-dense region In biology and medicine epithelium is a tissue composed of cells that line the cavities and surfaces of structures throughout the body Only those thymocytes that bind the MHC/antigen complex with adequate affinity will receive a vital "survival signal. " Developing thymocytes that do not have adequate affinity cannot serve useful functions in the body; the cells must be able to interact with MHC and peptide complexes in order to affect immune responses. Therefore, the other thymocytes with low affinity die by apoptosis (programmed cell death), and their remains are engulfed by macrophages. Thymocytes are T cell precursors which develop in the Thymus. Macrophages ( Greek: "big eaters" from makros "large" + phagein "eat" ( Mø) are cells within the tissues that This process is called positive selection.

Whether a thymocyte becomes a CD4+ cell or a CD8+ cell is also determined during positive selection. Double-positive cells that are positively selected on MHC class II molecules will become CD4+ cells, and cells positively selected on MHC class I molecules become CD8+ cells.

Note that this process does not remove from the population thymocytes that would cause autoimmunity or a reaction with one's own cells. Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which results in an immune response against its own cells and tissues The removal of such cells is dealt with by negative selection, which is discussed below.

Negative selection

Negative selection selects against cells reacting against self peptides presented by MHC.

Thymocytes that survive positive selection migrate towards the boundary of the thymic cortex and thymic medulla. Thymocytes are T cell precursors which develop in the Thymus. While in the medulla, they are again presented with self-antigen in complex with MHC molecules on antigen-presenting cells (APCs) such as dendritic cells and macrophages. See also Antigen presentation An antigen-presenting cell ( APC) or accessory cell is a cell that displays foreign Antigen complexed Dendritic cells (DCs are Immune cells and form part of the Mammalian Immune system. Macrophages ( Greek: "big eaters" from makros "large" + phagein "eat" ( Mø) are cells within the tissues that Thymocytes that interact too strongly with the antigen receive an apoptosis signal that causes their death; the vast majority of all thymocytes initially produced end up dying during thymic selection. A small minority of the surviving cells are selected to become regulatory T cells. Regulatory T cells (sometimes known as suppressor T cells) are a specialized subpopulation of T cells that act to suppress activation of the Immune system The remaining cells will then exit the thymus as mature naive T cells. A naive T cell or Th0 cell is a T cell that has differentiated in Bone marrow, and successfully undergone the positive and negative processes of central This process is called negative selection, an important mechanism of immunological tolerance that prevents the formation of self-reactive T cells capable of generating autoimmune disease in the host. Immune or immunological tolerance is the process by which the Immune system does not attack an Antigen. Autoimmune diseases arise from an overactive Immune response of the body against substances and tissues normally present in the body

T cell maturation paradox

Positive and negative selection should theoretically kill all developing T cells. The first stage of selection kills all T cells that do not interact with self-MHC, while the second stage selection kills all cells that do. This poses the question: How do we have immunity at all? Currently, two models attempt to explain this:

1. Differential Avidity Hypothesis - States that the strength of signal dictates the fate of the T cell. The Differential Avidity Hypothesis (or simply Avidity Hypothesis is one of two models that attempt to explain how humans have immunity despite such aggressive selection (positive and
2. Differential Signaling Hypothesis- States that signals transduced differ at each stage. The Differential Signaling Hypothesis is one of two models that attempt to explain how humans have immunity despite such aggressive selection (positive and negative to kill developing

T cell maturation

Maturation of T Cells occurs in the thymus. The first step is the rearrangement of the variable, joining, and constant region genes of the chain of the T cell antigen receptor in a way very similar to that of heavy chain rearrangement needed for immunoglobulin synthesis. In fact, the same enzymes are used for both.

Production of a functional TCR chain, signals expression of both CD4 and CD8 on the cell surface. This induces the genetic rearrangements needed to produce a functional TCR chain and an increase in TCR membrane expression. CD3 is then expressed, which produces a functional TCR complex (to be described later).

At this point, some of the T cells stop making CD8, so only CD4 remains on their cell membrane. The others undergo the reverse process, so they express only CD8. T cells then learn to not attack self tissues and to respond to antigen only if it is associated with a self histocompatibility antigen. This requires two steps:

• First, the immature, but CD4 or CD8 positive T cells are exposed to cells in the thymus, which have class I and class II histocompatibility antigens on them. T cells which are able to bind to one or the other of these antigens are protected, whereas the others die.
• Second, the cells that survive the above selection process are exposed to self antigens that have been taken up and associated with either class I or class II MHC antigen. Those that bind at this stage die by apoptosis.

The cells that survive are those that recognize non-self antigens associated with MHC antigens. After a little more maturation, they exit the thymus to perform their role in immune responses.

T cell activation

Although the specific mechanisms of activation vary slightly between different types of T cells, the "two-signal model" in CD4+ T cells holds true for most. Activation of CD4+ T cells occurs through the engagement of both the T cell receptor and CD28 on the T cell by the Major histocompatibility complex peptide and B7 family members on the APC, respectively. The T cell receptor or TCR is a molecule found on the surface of T lymphocytes (or T cells that is in general responsible for recognizing Antigens bound CD28 is one of the Molecules expressed on T cells that provide co-stimulatory signals which are required for T cell activation The major histocompatibility complex ( MHC) is a large genomic region or Gene family found in most Vertebrates It is the most gene-dense region Peptides (from the Greek πεπτίδια, "small digestibles" are short Polymers formed from the linking in a defined order of α- Amino B7 is a type of Peripheral membrane protein found on activated Antigen presenting cells (APC that when paired with either a CD28 or CD152 ( See also Antigen presentation An antigen-presenting cell ( APC) or accessory cell is a cell that displays foreign Antigen complexed Both are required for production of an effective immune response; in the absence of CD28 co-stimulation, T cell receptor signalling alone results in anergy. During the activation of T cells co-stimulation is often crucial to the development of an effective immune response. The signalling pathways downstream from both CD28 and the T cell receptor involve many proteins. CD28 is one of the Molecules expressed on T cells that provide co-stimulatory signals which are required for T cell activation

The first signal is provided by binding of the T cell receptor to a short peptide presented by the major histocompatibility complex (MHC) on another cell. This ensures that only a T cell with a TCR specific to that peptide is activated. The partner cell is usually a professional antigen presenting cell (APC), usually a dendritic cell in the case of naïve responses, although B cells and macrophages can be important APCs. Dendritic cells (DCs are Immune cells and form part of the Mammalian Immune system. A naive T cell or Th0 cell is a T cell that has differentiated in Bone marrow, and successfully undergone the positive and negative processes of central The peptides presented to CD8+ T cells by MHC class I molecules are 8-9 amino acids in length; the peptides presented to CD4+ cells by MHC class II molecules are longer, as the ends of the binding cleft of the MHC class II molecule are open. CD8 ( Cluster of differentiation 8 is a transmembrane Glycoprotein that serves as a Co-receptor for the T cell receptor (TCR CD4 ( Cluster of differentiation 4 is a Glycoprotein expressed on the surface of T helper cells, Regulatory T cells, Monocytes,

The second signal comes from co-stimulation, in which surface receptors on the APC are induced by a relatively small number of stimuli, usually products of pathogens, but sometimes breakdown products of cells, such as necrotic-bodies or heat-shock proteins. Necrosis (in Greek Νεκρός = "dead" is the name given to unnatural Death of cells and living tissue. Heat shock proteins ( HSP) are a group of Proteins whose expression is increased when the cells are exposed to elevated temperatures or other stress The only co-stimulatory receptor expressed constitutively by naïve T cells is CD28, so co-stimulation for these cells comes from the CD80 and CD86 proteins on the APC. CD28 is one of the Molecules expressed on T cells that provide co-stimulatory signals which are required for T cell activation The protein CD80 ( C luster of D ifferentiation The protein CD86 ( C luster of D ifferentiation 86) is a molecule expressed on antigen-presenting cells that provide costimulatory signals necessary for Other receptors are expressed upon activation of the T cell, such as OX40 and ICOS, but these largely depend upon CD28 for their expression. CD134, also known as OX40 is a member of the TNFR -superfamily of receptors which is not constitutively expressed on resting naïve T cells, unlike CD28 Inducible T-cell co-stimulator, also known as ICOS, is a human Gene. CD28 is one of the Molecules expressed on T cells that provide co-stimulatory signals which are required for T cell activation The second signal licenses the T cell to respond to an antigen. Without it, the T cell becomes anergic, and it becomes more difficult for it to activate in future. This mechanism prevents inappropriate responses to self, as self-peptides will not usually be presented with suitable co-stimulation.

The T cell receptor exists as a complex of several proteins. The T cell receptor or TCR is a molecule found on the surface of T lymphocytes (or T cells that is in general responsible for recognizing Antigens bound The actual T cell receptor is composed of two separate peptide chains, which are produced from the independent T cell receptor alpha and beta (TCRα and TCRβ) genes. The other proteins in the complex are the CD3 proteins: CD3εγ and CD3εδ heterodimers and, most important, a CD3ζ homodimer, which has a total of six ITAM motifs. In Immunology, the CD3 Antigen (CD stands for Cluster of differentiation) is a protein complex and is composed of four distinct chains An immunoreceptor tyrosine-based activation motif (ITAM is a conserved sequence of four Amino acids that is repeated twice in the cytoplasmic tails of certain cell surface proteins The ITAM motifs on the CD3ζ can be phosphorylated by Lck and in turn recruit ZAP-70. Lck (or leukocyte-specific protein tyrosine kinase) is a Protein that is found inside specialized cells of the Immune system called ZAP-70 is an abbreviation for Zeta-chain-associated protein kinase 70 (70 is the molecular weight in KDa) Lck and/or ZAP-70 can also phosphorylate the tyrosines on many other molecules, not least CD28, Trim, LAT and SLP-76, which allows the aggregation of signalling complexes around these proteins. Tyrosine (abbreviated as Tyr or Y) or 4-hydroxyphenylalanine, is one of the 20 Amino acids that are used by cells to synthesize CD28 is one of the Molecules expressed on T cells that provide co-stimulatory signals which are required for T cell activation Lymphocyte cytosolic protein 2 (SH2 domain containing leukocyte protein of 76kDa, also known as LCP2 or SLP-76, is a gene which encodes a Signal transducing

Phosphorylated LAT recruits SLP-76 to the membrane, where it can then bring in PLCγ, VAV1, Itk and potentially PI3K. Linker of Activated T cells (LAT is a transmembrane adapter protein associated with glycosphingolipid-enriched microdomains ( GEMs. Lymphocyte cytosolic protein 2 (SH2 domain containing leukocyte protein of 76kDa, also known as LCP2 or SLP-76, is a gene which encodes a Signal transducing Phospholipase C is a class of Enzymes that cleave Phospholipids just before the Phosphate group (see Figure Vav 1 oncogene, also known as VAV1, is a human Gene. Itk is a framework for building mega-widgets using the Tcl object system Phosphoinositide 3-kinases (PI 3-kinases or PI3Ks are a family of related enzymes that are capable of phosphorylating the 3 position Hydroxyl group of the Inositol Both PLCγ and PI3K act on PI(4,5)P2 on the inner leaflet of the membrane to create the active intermediaries diacylglycerol (DAG), inositol-1,4,5-trisphosphate (IP3), and phosphatidlyinositol-3,4,5-trisphosphate (PIP3). Phospholipase C is a class of Enzymes that cleave Phospholipids just before the Phosphate group (see Figure Phosphoinositide 3-kinases (PI 3-kinases or PI3Ks are a family of related enzymes that are capable of phosphorylating the 3 position Hydroxyl group of the Inositol Phosphatidylinositol (345-trisphosphate (PtdIns(345 P 3 commonly abbreviated to PIP3 is the product of the class I Phosphoinositide DAG binds and activates some PKCs, most important, in T cells PKCθ, a process important for activating the transcription factors NF-κB and AP-1. Protein kinase C ('PKC') is a family of protein kinases consisting of ~10 Isozymes. NF-κB ( nuclear factor-kappa B) is a protein complex that is a Transcription factor. IP3 is released from the membrane by PLCγ and diffuses rapidly to activate receptors on the ER, which induce the release of calcium. Phospholipase C is a class of Enzymes that cleave Phospholipids just before the Phosphate group (see Figure The endoplasmic reticulum (Greek endo = "within" (prefix plásma = "formed entity" Latin reticulum = "little net" or ER, is an Organelle Calcium (ˈkælsiəm is the Chemical element with the symbol Ca and Atomic number 20 The released calcium then activates calcineurin, and calcineurin activates NFAT, which then translocates to the nucleus. Protein phosphatase 3 (formerly 2B catalytic subunit alpha isoform, also known as PPP3CA, is a human Gene. Protein phosphatase 3 (formerly 2B catalytic subunit alpha isoform, also known as PPP3CA, is a human Gene. Nuclear factor of activated T-cells ( NFAT) is a general name applied to a family of Transcription factors shown to be important in Immune response. NFAT is a transcription factor, which activates the transcription of a pleiotropic set of genes, most notable, IL-2, a cytokine that promotes long term proliferation of activated T cells. In the field of Molecular biology, a transcription factor (sometimes called a sequence-specific DNA binding factor is a Protein that binds to specific sequences

See also

• Apoptosis
• Naive T cell
• Memory T cell
• γδ T cell

References

External links

• Immunobiology, 5th Edition
• niaid.nih.gov – The Immune System
• T-cell Antigen Recognition Group - Cardiff University