A T cell is a type of
lymphocyte
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...
. T cells are one of the important
white blood cell
White blood cells, also called leukocytes or leucocytes, are the cell (biology), cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and de ...
s of the immune system and play a central role in the
adaptive immune response
The adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system ...
. T cells can be distinguished from other lymphocytes by the presence of a
T-cell receptor
The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding b ...
(TCR) on their
cell surface
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
.
T cells are born from
hematopoietic stem cells
Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within ...
, found in the
bone marrow
Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...
. Developing T cells then migrate to the
thymus
The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or ''T cells'' mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. ...
gland to develop (or mature). T cells derive their name from the
thymus
The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or ''T cells'' mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. ...
. After migration to the thymus, the precursor cells mature into several distinct types of T cells. T cell differentiation also continues after they have left the thymus. Groups of specific, differentiated T cell subtypes have a variety of important functions in controlling and shaping the
immune response
An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which could ...
.
One of these functions is immune-mediated cell death, and it is carried out by two major subtypes:
CD8+ "killer" and
CD4+ "helper" T cells. (These are named for the presence of the cell surface proteins
CD8
CD8 (cluster of differentiation 8) is a transmembrane glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). Along with the TCR, the CD8 co-receptor plays a role in T cell signaling and aiding with cytotoxic T cell-antigen int ...
or
CD4.) CD8+ T cells, also known as "killer T cells", are
cytotoxic
Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa'').
Cell physiology
Treating cells ...
– this means that they are able to directly kill virus-infected cells, as well as cancer cells. CD8+ T cells are also able to use small signaling proteins, known as
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s, to recruit other types of cells when mounting an immune response. A different population of T cells, the CD4+ T cells, function as "helper cells". Unlike CD8+ killer T cells, the CD4+ helper T (T
H) cells function by further activating
memory B cell
In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quiescen ...
s and cytotoxic T cells, which leads to a larger immune response. The specific adaptive immune response regulated by the T
H cell depends on its subtype, which is distinguished by the types of cytokines they secrete.
Regulatory T cell
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 immunosup ...
s are yet another distinct population of T cells that provide the critical mechanism of
tolerance, whereby immune cells are able to distinguish invading cells from "self". This prevents immune cells from inappropriately reacting against one's own cells, known as an "
autoimmune
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". P ...
" response. For this reason, these regulatory T cells have also been called "suppressor" T cells. These same regulatory T cells can also be co-opted by cancer cells to prevent the recognition of, and an immune response against, tumor cells.
Development
Origin, early development and migration to the thymus
All T cells originate from c-kit
+Sca1
+ haematopoietic stem cell
Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within t ...
s (HSC) which reside in the bone marrow. In some cases, the origin might be the fetal
liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
during
embryonic development
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...
. The HSC then differentiate into multipotent progenitors (MPP) which retain the potential to become both
myeloid
Myeloid tissue, in the bone marrow sense of the word '' myeloid'' ('' myelo-'' + ''-oid''), is tissue of bone marrow, of bone marrow cell lineage, or resembling bone marrow, and myelogenous tissue (''myelo-'' + '' -genous'') is any tissue of, ...
and
lymphoid cells
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic adapt ...
. The process of differentiation then proceeds to a common lymphoid progenitor (CLP), which can only differentiate into T, B or NK cells. These CLP cells then migrate via the blood to the thymus, where they
engraft:. Henceforth they are known as
thymocyte
A Thymocyte is an immune cell present in the thymus, before it undergoes transformation into a T cell. Thymocytes are produced as stem cells in the bone marrow and reach the thymus via the blood. Thymopoiesis describes the process which turns thymo ...
s, the immature stage of a T cell.
The earliest cells which arrived in the thymus are commonly termed ''double-negative'', as they express neither the
CD4 nor
CD8
CD8 (cluster of differentiation 8) is a transmembrane glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). Along with the TCR, the CD8 co-receptor plays a role in T cell signaling and aiding with cytotoxic T cell-antigen int ...
co-receptor. The newly arrived CLP cells are CD4
−CD8
−CD44
+CD25
−ckit
+ cells, and are termed early thymic progenitor (ETP) cells. These cells will then undergo a round of division and
downregulate
In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary proc ...
c-kit and are termed ''double-negative one'' (DN1) cells. To become T cells, the thymocytes must undergo multiple DN stages as well as positive selection and negative selection.
Double negative thymocytes can be identified by the surface expression of
CD2
CD2 (cluster of differentiation 2) is a cell adhesion molecule found on the surface of T cells and natural killer (NK) cells.
It has also been called T-cell surface antigen T11/Leu-5, LFA-2, LFA-3 receptor, erythrocyte receptor and rosette rece ...
,
CD5 and
CD7
CD7 (Cluster of Differentiation 7) is a protein that in humans is encoded by the ''CD7'' gene.
Function
This gene encodes a transmembrane protein which is a member of the immunoglobulin superfamily. This protein is found on thymocytes and matur ...
. Still during the double negative stages,
CD34
CD34 is a transmembrane phosphoglycoprotein protein encoded by the CD34 gene in humans, mice, rats and other species.
CD34 derives its name from the cluster of differentiation protocol that identifies cell surface antigens. CD34 was first descri ...
expression stops and
CD1
CD1 (cluster of differentiation 1) is a family of glycoproteins expressed on the surface of various human antigen-presenting cells. They are related to the class I MHC molecules, and are involved in the presentation of lipid antigens to T ...
is expressed. Expression of both CD4 and CD8 makes them ''double positive'', and matures into either CD4+ or CD8+ cells.
TCR development
A critical step in T cell maturation is making a functional T cell receptor (TCR). Each mature T cell will ultimately contain a unique TCR that reacts to a random pattern, allowing the immune system to recognize many different types of
pathogen
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
s. This process is essential in developing immunity to threats that the immune system has not encountered before, since due to random variation there will always be at least one TCR to match any new pathogen.
A thymocyte can only become an active T cell when it survives the process of developing a functional TCR. The TCR consists of two major components, the alpha and beta chains. These both contain random elements designed to produce a wide variety of different TCRs, but due to this huge variety they must be tested to make sure they work at all. First, the thymocytes attempt to create a functional beta chain, testing it against a 'mock' alpha chain. Then they attempt to create a functional alpha chain. Once a working TCR has been produced, the cells then must test if their TCR will identify threats correctly, and to do this it is required to recognize the body’s
major histocompatibility complex
The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are calle ...
(MHC) in a process known as positive selection. The thymocyte must also ensure that it does not react adversely to "self"
antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
s, called negative selection. If both positive and negative selection are successful, the TCR becomes fully operational and the thymocyte becomes a T cell.
TCR β-chain selection
At the DN2 stage (CD44
+CD25
+), cells upregulate the recombination genes RAG1 and RAG2 and re-arrange the
TCRβ locus, combining
V-D-J recombination and constant region genes in an attempt to create a functional TCRβ chain. As the developing thymocyte progresses through to the DN3 stage (CD44
−CD25
+), the thymocyte expresses an invariant α-chain called pre-Tα alongside the TCRβ gene. If the rearranged β-chain successfully pairs with the invariant α-chain, signals are produced which cease rearrangement of the β-chain (and silence the alternate allele). Although these signals require the pre-TCR at the cell surface, they are independent of ligand binding to the pre-TCR. If the chains successfully pair a pre-TCR forms, and the cell downregulates CD25 and is termed a DN4 cell (CD25
−CD44
−). These cells then undergo a round of proliferation, and begin to re-arrange the TCRα locus during the ''double-positive'' stage.
Positive selection
The process of positive selection takes 3 to 4 days and occurs in the thymic cortex. Double-positive thymocytes (CD4
+/CD8
+) migrate deep into the
thymic cortex, where they are presented with self-
antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
s. These self-antigens are expressed by
thymic cortical epithelial cells on MHC molecules, which reside on the surface of cortical epithelial cells. Only thymocytes that interact well with MHC-I or MHC-II will receive a vital "survival signal", while those that cannot interact strongly enough will receive no signal and die from neglect. This process ensures that the surviving thymocytes will have an 'MHC affinity' that means they can serve useful functions in the body, responding to MHC molecules to assist immune responses. The vast majority of developing thymocytes will not pass positive selection, and die during this process.
A thymocyte's fate is determined during positive selection. Double-positive cells (CD4
+/CD8
+) that interact well with MHC ''class II'' molecules will eventually become CD4
+ "helper" cells, whereas thymocytes that interact well with MHC ''class I'' molecules mature into CD8
+ "killer" cells. A thymocyte becomes a CD4
+ cell by down-regulating expression of its CD8 cell surface receptors. If the cell does not lose its signal, it will continue downregulating CD8 and become a CD4
+, both CD8
+ and CD4
+ cells are now ''single positive'' cells.
This process does not filter for thymocytes that may cause
autoimmunity
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". ...
. The potentially autoimmune cells are removed by the following process of negative selection, which occurs in the thymic medulla.
Negative selection
Negative selection removes thymocytes that are capable of strongly binding with "self" MHC molecules. Thymocytes that survive positive selection migrate towards the boundary of the cortex and medulla in the thymus. While in the medulla, they are again presented with a self-antigen presented on the MHC complex of
medullary thymic epithelial cells (mTECs).
mTECs must be
Autoimmune regulator
The autoimmune regulator (''AIRE'') is a protein that in humans is encoded by the ''AIRE'' gene. It is a 13kb gene on chromosome 21q22.3 that has 545 amino acids. AIRE is a transcription factor expressed in the medulla (inner part) of the thymus. ...
positive (AIRE
+) to properly express self-antigens from all tissues of the body on their MHC ''class I'' peptides. Some mTECs are
phagocytosed
Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is c ...
by
thymic dendritic cells; this makes them AIRE
− antigen presenting cells
An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using ...
(APCs), allowing for presentation of self-antigens on MHC ''class II'' molecules (positively selected CD4
+ cells must interact with these MHC class II molecules, thus APCs, which possess MHC class II, must be present for CD4
+ T-cell negative selection). Thymocytes that interact too strongly with the self-antigen receive an
apoptotic
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes includ ...
signal that leads to cell death. However, some of these cells are selected to become
Treg
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 immunosu ...
cells. The remaining cells exit the thymus as mature
naive T cell
In immunology, a naive T cell (Th0 cell) is a T cell that has differentiated in the thymus, and successfully undergone the positive and negative processes of central selection in the thymus. Among these are the naive forms of helper T cells ( CD ...
s, also known as recent thymic emigrants. This process is an important component of
central tolerance
In immunology, central tolerance (also known as negative selection) is the process of eliminating any ''developing'' T or B lymphocytes that are autoreactive, i.e. reactive to the body itself. Through elimination of autoreactive lymphocytes, to ...
and serves to prevent the formation of self-reactive T cells that are capable of inducing autoimmune diseases in the host.
TCR development summary
β-selection is the first checkpoint, where thymocytes that are able to form a functional pre-TCR (with an invariant alpha chain and a functional beta chain) are allowed to continue development in the thymus. Next, positive selection checks that thymocytes have successfully rearranged their TCRα locus and are capable of recognizing MHC molecules with appropriate affinity. Negative selection in the medulla then eliminates thymocytes that bind too strongly to self-antigens expressed on MHC molecules. These selection processes allow for tolerance of self by the immune system. Typical naive T cells that leave the thymus (via the corticomedullary junction) are self-restricted, self-tolerant, and single positive.
Thymic output
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.
The thymus contributes fewer cells as a person ages. As the thymus shrinks by about 3%
a year throughout middle age, a corresponding fall in the thymic production of naive T cells occurs, leaving peripheral T cell expansion and regeneration to play a greater role in protecting older people.
Types of T cell
T cells are grouped into a series of subsets based on their function. CD4 and CD8 T cells are selected in the thymus, but undergo further differentiation in the periphery to specialized cells which have different functions. T cell subsets were initially defined by function, but also have associated gene or protein expression patterns.
Conventional adaptive T cells
Helper CD4+ T cells
T helper 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 considere ...
s (T
H cells) assist other lymphocytes, including the maturation of
B cell
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
s into
plasma cell
Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B lymphocytes and secrete large quantities of proteins called antibodies in response to being presented specific substan ...
s and
memory B cell
In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quiescen ...
s, and activation of
cytotoxic T cells
A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular p ...
and
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s. These cells are also known as CD4
+ T cells as they express the
CD4 glycoprotein on their surfaces. Helper T cells become activated when they are presented with
peptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
A ...
antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
s by
MHC class II
MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial ce ...
molecules, which are expressed on the surface of
antigen-presenting cell
An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using ...
s (APCs). Once activated, they divide rapidly and secrete
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s that regulate or assist the immune response. These cells can differentiate into one of several subtypes, which have different roles. Cytokines direct T cells into particular subtypes.
Cytotoxic CD8+ T cells
Cytotoxic T cell
A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pa ...
s (T
C cells, CTLs, T-killer cells, killer T cells) destroy virus-infected cells and tumor cells, and are also implicated in
transplant rejection. These cells are defined by the expression of the
CD8
CD8 (cluster of differentiation 8) is a transmembrane glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). Along with the TCR, the CD8 co-receptor plays a role in T cell signaling and aiding with cytotoxic T cell-antigen int ...
protein on their cell surface. Cytotoxic T cells recognize their targets by binding to short peptides (8-11
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
s in length) associated with
MHC class I
MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules (the other being MHC class II) and are found on the cell surface of all nucleated cells in the bodies of vertebrates. They also occur on plat ...
molecules, present on the surface of all nucleated cells. Cytotoxic T cells also produce the key cytokines IL-2 and IFNγ. These cytokines influence the effector functions of other cells, in particular macrophages and NK cells.
Memory T cells
Antigen-naive T cells expand and differentiate into memory and
effector T cells
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 consider ...
after they encounter their cognate antigen within the context of an MHC molecule on the surface of a professional antigen presenting cell (e.g. a dendritic cell). Appropriate co-stimulation must be present at the time of antigen encounter for this process to occur. Historically, memory T cells were thought to belong to either the effector or central memory subtypes, each with their own distinguishing set of cell surface markers (see below). Subsequently, numerous new populations of memory T cells were discovered including tissue-resident memory T (Trm) cells, stem memory TSCM cells, and virtual memory T cells. The single unifying theme for all
memory T cell
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.
Function
Antigen-specific memory T cells specific to viruses or other microbial molecules can be found in both ...
subtypes is that they are long-lived and can quickly expand to large numbers of effector T cells upon re-exposure to their cognate antigen. By this mechanism they provide the immune system with "memory" against previously encountered pathogens. Memory T cells may be either CD4
+ or CD8
+ and usually express
CD45RO.
Memory T cell subtypes:
* Central memory T cells (T
CM cells) express CD45RO,
C-C chemokine receptor type 7 (CCR7), and
L-selectin
L-selectin, also known as CD62L, is a cell adhesion molecule found on the cell surface of leukocytes, and the blastocyst. It is coded for in the human by the ''SELL'' gene. L-selectin belongs to the selectin family of proteins, which recognize s ...
(CD62L). Central memory T cells also have intermediate to high expression of
CD44
The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the ''CD44'' gene on chromosome 11. CD44 has been referred to as HCAM (homing cell adhes ...
. This memory subpopulation is commonly found in the
lymph node
A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that inclu ...
s and in the peripheral circulation. (Note- CD44 expression is usually used to distinguish murine naive from memory T cells).
* Effector memory T cells (T
EM cells and T
EMRA cells) express CD45RO but lack expression of CCR7 and
L-selectin
L-selectin, also known as CD62L, is a cell adhesion molecule found on the cell surface of leukocytes, and the blastocyst. It is coded for in the human by the ''SELL'' gene. L-selectin belongs to the selectin family of proteins, which recognize s ...
. They also have intermediate to high expression of
CD44
The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the ''CD44'' gene on chromosome 11. CD44 has been referred to as HCAM (homing cell adhes ...
. These memory T cells lack lymph node-homing receptors and are thus found in the peripheral circulation and tissues. T
EMRA stands for terminally differentiated effector memory cells re-expressing CD45RA, which is a marker usually found on naive T cells.
*
Tissue-resident memory T cells (T
RM) occupy tissues (skin, lung, etc.) without recirculating. One cell surface marker that has been associated with T
RM is the intern αeβ7, also known as CD103.
*
Virtual memory T cells (T
VM) differ from the other memory subsets in that they do not originate following a strong clonal expansion event. Thus, although this population as a whole is abundant within the peripheral circulation, individual virtual memory T cell clones reside at relatively low frequencies. One theory is that homeostatic proliferation gives rise to this T cell population. Although CD8 virtual memory T cells were the first to be described, it is now known that CD4 virtual memory cells also exist.
Regulatory CD4+ T cells
Regulatory T cell
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 immunosup ...
s are crucial for the maintenance of
immunological tolerance
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 ...
. Their major role is to shut down T cell–mediated immunity toward the end of an immune reaction and to suppress
autoreactive T cell
In immunology, reactive lymphocytes or variant lymphocytes are cytotoxic (CD8+) lymphocytes that become large as a result of antigen stimulation. Typically, they can be more than 30 Micrometre, μm in diameter with varying size and shape.
The C ...
s that escaped the process of negative selection in the thymus.
Two major classes of CD4
+ T
reg cells have been described—FOXP3
+ T
reg cells and FOXP3
− T
reg cells.
Regulatory T cells can develop either during normal development in the thymus, and are then known as thymic Treg cells, or can be induced peripherally and are called peripherally derived Treg cells. These two subsets were previously called "naturally occurring" and "adaptive" (or "induced"), respectively.
Both subsets require the expression of the
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
FOXP3
FOXP3 ( forkhead box P3), also known as scurfin, is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator of the regulatory pathway in the development and function of ...
which can be used to identify the cells. Mutations of the ''FOXP3'' gene can prevent regulatory T cell development, causing the fatal
autoimmune disease
An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
IPEX.
Several other types of T cells have suppressive activity, but do not express FOXP3 constitutively. These include
Tr1 and
Th3 cells, which are thought to originate during an immune response and act by producing suppressive molecules. Tr1 cells are associated with IL-10, and Th3 cells are associated with
TGF-beta
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other sign ...
. Recently,
Th17 cells have been added to this list.
Innate-like T cells
Innate-like T cells or unconventional T cells represent some subsets of T cells that behave differently in immunity. They trigger rapid immune responses, regardless of the major histocompatibility complex (MHC) expression, unlike their conventional counterparts (CD4 T helper cells and CD8 cytotoxic T cells), which are dependent on the recognition of peptide antigens in the context of the MHC molecule. Overall, there are three large populations of unconventional T cells: NKT cells, MAIT cells, and gammadelta T cells. Now, their functional roles are already being well established in the context of infections and cancer. Furthermore, these T cell subsets are being translated into many therapies against malignancies such as leukemia, for example.
Natural killer T cell
Natural killer T cell
Natural killer T (NKT) cells are a heterogeneous group of T cells that share properties of both T cells and natural killer cells. Many of these cells recognize the non-polymorphic CD1d molecule, an antigen-presenting molecule that binds self and ...
s (NKT cells – not to be confused with
natural killer cell
Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and repres ...
s of the innate immune system) bridge the
adaptive immune system
The adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system ...
with the
innate immune system
The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...
. Unlike conventional T cells that recognize protein peptide antigens presented by
major histocompatibility complex
The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are calle ...
(MHC) molecules, NKT cells recognize glycolipid antigens presented by
CD1d
CD1D is the human gene that encodes the protein CD1d, a member of the CD1 (cluster of differentiation 1) family of glycoproteins expressed on the surface of various human antigen-presenting cells. They are non-classical MHC proteins, related to ...
. Once activated, these cells can perform functions ascribed to both helper and cytotoxic T cells: cytokine production and release of cytolytic/cell killing molecules. They are also able to recognize and eliminate some tumor cells and cells infected with herpes viruses.
Mucosal associated invariant T cells
Mucosal associated invariant T (MAIT) cells display