CTLA-4 or CTLA4 (cytotoxic T-lymphocyte-associated protein 4), also known as CD152 (
cluster of differentiation
The cluster of differentiation (also known as cluster of designation or classification determinant and often abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules providing targets for immunophen ...
152), is a
protein receptor
In biochemistry and pharmacology, receptors are chemical structures, composed of protein, that receive and transduce signals that may be integrated into biological systems. These signals are typically chemical messengers which bind to a recepto ...
that functions as an
immune checkpoint
Immune checkpoints are regulators of the immune system. These pathways are crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately. However, some cancers can protect themselves from attack by stimula ...
and downregulates
immune responses
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 ...
. CTLA-4 is constitutively expressed in
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 immunosu ...
s but only upregulated in conventional
T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
s after activation – a phenomenon which is particularly notable in cancers.
It acts as an "off" switch when bound to
CD80
The Cluster of differentiation 80 (also CD80 and B7-1) is a B7, type I membrane protein in the immunoglobulin superfamily, with an extracellular immunoglobulin constant-like domain and a variable-like domain required for receptor binding. It is cl ...
or
CD86
Cluster of Differentiation 86 (also known as CD86 and B7-2) is a protein constitutively expressed on dendritic cells, Langerhans cells, macrophages, B-cells (including memory B-cells), and on other antigen-presenting cells. Along with CD80, CD8 ...
on the surface of
antigen-presenting cells.
The CTLA-4 protein is encoded by the ''Ctla-4'' gene in mice
and the ''CTLA-4'' gene in humans.
History
CTLA-4 was first identified in 1991 as a second receptor for the T cell costimulation ligand
B7. In November 1995, the labs of
Tak Wah Mak
Tak Wah Mak, (; born October 4, 1946, in China) is a Canadian medical researcher, geneticist, oncologist, and biochemist. He first became widely known for his discovery of the T-cell receptor in 1983 and pioneering work in the genetics of immun ...
and Arlene H. Sharpe independently published their findings on the discovery of the function of CTLA-4 as a negative regulator of T-cell activation, by
knocking out the gene in mice.
Previous studies from several labs had used methods which could not definitively define the function of CTLA-4, and were contradictory.
Function
CTLA-4 is a member of the
immunoglobulin superfamily
The immunoglobulin superfamily (IgSF) is a large protein superfamily of cell surface and soluble proteins that are involved in the recognition, binding, or adhesion processes of cells. Molecules are categorized as members of this superfamily ...
that is expressed by activated
T cells
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell re ...
and transmits an inhibitory signal to
T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
s. CTLA-4 is homologous to the T-cell co-stimulatory protein,
CD28, and both molecules bind to
CD80
The Cluster of differentiation 80 (also CD80 and B7-1) is a B7, type I membrane protein in the immunoglobulin superfamily, with an extracellular immunoglobulin constant-like domain and a variable-like domain required for receptor binding. It is cl ...
and
CD86
Cluster of Differentiation 86 (also known as CD86 and B7-2) is a protein constitutively expressed on dendritic cells, Langerhans cells, macrophages, B-cells (including memory B-cells), and on other antigen-presenting cells. Along with CD80, CD8 ...
, also called B7-1 and B7-2 respectively, on antigen-presenting cells. CTLA-4 binds CD80 and CD86 with greater affinity and avidity than CD28 thus enabling it to outcompete CD28 for its ligands. CTLA-4 transmits an inhibitory signal to T cells,
whereas CD28 transmits a stimulatory signal.
CTLA-4 is also found in
regulatory T cells (Tregs) and contributes to their inhibitory function. T cell activation through the T cell receptor and CD28 leads to increased expression of CTLA-4.
The mechanism by which CTLA-4 acts in T cells remains somewhat controversial. Biochemical evidence suggested that CTLA-4 recruits a phosphatase to the T cell receptor (TCR), thus attenuating the signal.
This work remains unconfirmed in the literature since its first publication. More recent work has suggested that CTLA-4 may function in vivo by capturing and removing CD80 and CD86 from the membranes of antigen-presenting cells, thus making these unavailable for triggering of CD28.
In addition to that, it has been found that dendritic cell (DC) - Treg interaction causes sequestration of
Fascin-1, an actin-bundling protein essential for immunological synapse formation and skews Fascin-1–dependent actin polarization in antigen presenting DCs toward the Treg cell adhesion zone. Although it is reversible upon T regulatory cell disengagement, this sequestration of essential cytoskeletal components causes a lethargic state of DCs, leading to reduced T cell priming. This suggests Treg-mediated immune suppression is a multi-step process. In addition to CTLA-4 CD80/CD86 interaction, fascin-dependent polarization of the cytoskeleton towards DC-Treg immune synapse may play a pivotal role.
CTLA-4 may also function via modulation of cell motility and/or signaling through PI3 kinase
Early multiphoton microscopy studies observing T-cell motility in intact lymph nodes appeared to give evidence for the so-called ‘reverse-stop signaling model’.
In this model CTLA-4 reverses the TCR-induced ‘stop signal’ needed for firm contact between T cells and antigen-presenting cells (APCs).
However, those studies compared CTLA-4 positive cells, which are predominantly regulatory cells and are at least partially activated, with CTLA-4 negative naive T cells. The disparity of these cells in multiple regards may explain some of these results. Other groups who have analyzed the effect of antibodies to CTLA-4 in vivo have concluded little or no effect upon motility in the context of anergic T-cells.
Antibodies to CTLA-4 may exert additional effects when used in vivo, by binding and thereby depleting regulatory T cells.
Structure
The protein contains an
extracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
V domain, a
transmembrane
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...
domain, and a
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
ic tail.
Alternate splice variants, encoding different
isoform
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...
s, have been characterized. The membrane-bound isoform functions as a
homodimer
In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' ha ...
interconnected by a
disulfide bond
In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
, while the soluble isoform functions as a monomer. The intracellular domain is similar to that of
CD28, in that it has no intrinsic catalytic activity and contains one YVKM motif able to bind
PI3K
Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
,
PP2A
Protein phosphatase 2 (PP2), also known as PP2A, is an enzyme that in humans is encoded by the ''PPP2CA'' gene. The PP2A heterotrimeric protein phosphatase is ubiquitously expressed, accounting for a large fraction of phosphatase activity in eu ...
and
SHP-2
Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in huma ...
and one proline-rich motif able to bind
SH3 containing proteins. The first role of CTLA-4 in inhibiting T cell responses seem to be directly via SHP-2 and PP2A dephosphorylation of TCR-proximal signalling proteins such as
CD3 and
LAT
Lat or LAT may refer to:
Places
* Lat, Fuman, village in Gilan Province, Iran
* Lat, Rasht, village in Gilan Province, Iran
* Lat, Mazandaran, village in Iran
* Lat-e Disar, village in Mazandaran Province, Iran
* Lat, Qazvin, village in I ...
. CTLA-4 can also affect signalling indirectly via competing with CD28 for CD80/86 binding. CTLA-4 can also bind
PI3K
Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
, although the importance and results of this interaction are uncertain.
Clinical significance
Variants in this gene have been associated with
Type 1 diabetes
Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar ...
,
Graves' disease
Graves' disease (german: Morbus Basedow), also known as toxic diffuse goiter, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyr ...
,
Hashimoto's thyroiditis
Hashimoto's thyroiditis, also known as chronic lymphocytic thyroiditis and Hashimoto's disease, is an autoimmune disease in which the thyroid gland is gradually destroyed. Early on, symptoms may not be noticed. Over time, the thyroid may enlarg ...
,
celiac disease
Coeliac disease (British English) or celiac disease (American English) is a long-term autoimmune disorder, primarily affecting the small intestine, where individuals develop intolerance to gluten, present in foods such as wheat, rye and barle ...
,
systemic lupus erythematosus
Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Comm ...
, thyroid-associated orbitopathy,
primary biliary cirrhosis and other
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 ...
s.
Polymorphisms of the CTLA-4 gene are associated with autoimmune diseases such as
rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...
, autoimmune thyroid disease and multiple sclerosis, though this association is often weak. In systemic lupus erythematosus (SLE), the splice variant sCTLA-4 is found to be aberrantly produced and found in the serum of patients with active SLE.
Germline haploinsufficiency
Germline
In biology and genetics, the germline is the population of a multicellular organism's cells that pass on their genetic material to the progeny (offspring). In other words, they are the cells that form the egg, sperm and the fertilised egg. They ...
haploinsufficiency
Haploinsufficiency in genetics describes a model of dominant gene action in diploid organisms, in which a single copy of the wild-type allele at a locus in heterozygous combination with a variant allele is insufficient to produce the wild-type ...
of CTLA-4 leads to CTLA-4 deficiency or
CHAI disease (CTLA4 haploinsufficiency with
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". ...
infiltration), a rare genetic disorder of the immune system. This may cause a dysregulation of the immune system and may result in lymphoproliferation, autoimmunity,
hypogammaglobulinemia
Hypogammaglobulinemia is a problem with the immune system in which not enough gamma globulins are produced in the blood (thus '' hypo-'' + ''gamma'' + ''globulin'' + '' -emia''). This results in a lower antibody count, which impairs the immune sys ...
, recurrent infections, and may slightly increase one’s risk of
lymphoma
Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlar ...
. CTLA-4 mutations have first been described by a collaboration between the groups of Dr. Gulbu Uzel, Dr. Steven Holland, and Dr. Michael Lenardo from the
National Institute of Allergy and Infectious Disease
The National Institute of Allergy and Infectious Diseases (NIAID, ) is one of the 27 institutes and centers that make up the National Institutes of Health (NIH), an agency of the United States Department of Health and Human Services (HHS). NIAID's ...
, Dr. Thomas Fleisher from the
NIH Clinical Center
The NIH Clinical Center is a hospital solely dedicated to clinical research at the National Institutes of Health campus in Bethesda, Maryland. The Clinical Center, known as Building 10, consists of the original part of the hospital, the Warren Gr ...
at the
National Institutes of Health
The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...
, and their collaborators in 2014.
In the same year a collaboration between the groups of Dr. Bodo Grimbacher, Dr. Shimon Sakaguchi, Dr. Lucy Walker and Dr. David Sansom and their collaborators described a similar phenotype.
CTLA-4 mutations are inherited in an
autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
manner. This means a person only needs one abnormal gene from one parent. The one normal copy is not enough to compensate for the one abnormal copy. Dominant inheritance means most families with CTLA-4 mutations have affected relatives in each
generation
A generation refers to all of the people born and living at about the same time, regarded collectively. It can also be described as, "the average period, generally considered to be about 20–30 years, during which children are born and gr ...
on the side of the family with the
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
.
Clinical and laboratory manifestations
Symptomatic patients with CTLA-4 mutations are characterized by an immune dysregulation syndrome including extensive
T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
infiltration in a number of organs, including the gut, lungs, bone marrow, central nervous system.
and kidneys. Most patients have diarrhea or
enteropathy
Enteropathy refers to any pathology of the intestine. Although enteritis specifically refers to an inflammation of the intestine, and is thus a more specific term than "enteropathy", the two phrases are sometimes used interchangeably.
__TOC__
Type ...
.
Lymphadenopathy and
hepatosplenomegaly
Hepatosplenomegaly (commonly abbreviated HSM) is the simultaneous enlargement of both the liver (hepatomegaly) and the spleen (splenomegaly). Hepatosplenomegaly can occur as the result of acute viral hepatitis, infectious mononucleosis, and hist ...
are also common, as is autoimmunity. The organs affected by autoimmunity vary but include
thrombocytopenia
Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients an ...
,
hemolytic anemia
Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular). This most commonly ...
,
thyroiditis
Thyroiditis is the inflammation of the thyroid gland. The thyroid gland is located on the front of the neck below the laryngeal prominence, and makes hormones that control metabolism.
Signs and symptoms
There are many different signs and sympto ...
, type I diabetes,
psoriasis
Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to complete ...
, and
arthritis
Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In som ...
. Respiratory infections are also common. Importantly, the clinical presentations and disease courses are variable with some individuals severely affected, whereas others show little manifestation of disease. This “
variable expressivity,” even within the same family, can be striking and may be explained by differences in lifestyle, exposure to pathogens, treatment efficacy, or other genetic modifiers.
This condition is described to have incomplete penetrance of disease.
Penetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also express an associated trait (the phenotype). In medical genetics, the penetrance of a disease-causing mutation is t ...
is said to be incomplete when some individuals fail to express the trait and seem completely asymptomatic, even though they carry the allele. The penetrance is estimated to be about 60%.
The clinical symptoms are caused by abnormalities of the immune system. Most patients develop reduced levels of at least one
immunoglobulin
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
isotype, and have low CTLA-4 protein expression in T regulatory cells, hyperactivation of effector T cells, low switched
memory B cells
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 quiesce ...
, and progressive loss of circulating B cells.
Treatment
Once a diagnosis is made, the treatment is based on an individual’s clinical condition and may include standard management for autoimmunity and immunoglobulin deficiencies. A study reported in 2016 treated a Korean CHAI disease patient with
abatacept
Abatacept, sold under the brand name Orencia, is a medication used to treat autoimmune diseases like rheumatoid arthritis, by interfering with the immune activity of T cells. It is a modified antibody.
Abatacept is a fusion protein composed of ...
, which is a
fusion protein of CTLA-4 and an antibody, and was able to control immune activity and improve patient symptoms. Regular administration of abatacept improved the patient’s severe anemia and diarrhea (3L/day) and brought 3-year-long hospitalization to an end.
Agonists to reduce immune activity
The comparatively higher binding affinity of CTLA-4 than CD28 has made it a potential therapy for
autoimmune diseases
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 ...
. Fusion proteins of CTLA-4 and antibodies (CTLA4-Ig) have been used in clinical trials for rheumatoid arthritis.
The fusion protein CTLA4-Ig is commercially available as Orencia (
abatacept
Abatacept, sold under the brand name Orencia, is a medication used to treat autoimmune diseases like rheumatoid arthritis, by interfering with the immune activity of T cells. It is a modified antibody.
Abatacept is a fusion protein composed of ...
). A second generation form of CTLA4-Ig known as
belatacept
Belatacept, sold under the brand name Nulojix, is a fusion protein composed of the Fc fragment of a human IgG1 immunoglobulin linked to the extracellular domain of CTLA-4, which is a molecule crucial in the regulation of T cell costimulation, s ...
was recently approved by the FDA based on favorable results from the randomized Phase III BENEFIT (Belatacept Evaluation of Nephroprotection and Efficacy as First Line Immunosuppression Trial) study. It was approved for renal transplantation in patients that are sensitized to
Epstein–Barr virus
The Epstein–Barr virus (EBV), formally called ''Human gammaherpesvirus 4'', is one of the nine known human herpesvirus types in the herpes family, and is one of the most common viruses in humans. EBV is a double-stranded DNA virus.
It is b ...
(EBV).
Antagonists to increase immune activity
Conversely, there is increasing interest in the possible therapeutic benefits of blocking CTLA-4 (using antagonistic antibodies against CTLA such as
ipilimumab
Ipilimumab, sold under the brand name Yervoy, is a monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.
Cytotoxic T lymphocytes (CTLs) can recogniz ...
—FDA approved for melanoma in 2011—as a means of inhibiting immune system tolerance to tumours and thereby providing a potentially useful immunotherapy strategy for patients with cancer).
This therapy was the first approved
immune checkpoint blockade
Cancer immunotherapy (sometimes called immuno-oncology) is the stimulation of the immune system to treat cancer, improving on the immune system's natural ability to fight the disease. It is an application of the basic research, fundamental resea ...
therapy.
Another (not yet approved) is
tremelimumab
Tremelimumab, sold under the brand name Imjudo, is a fully human monoclonal antibody against CTLA-4. It is an immune checkpoint blocker.
Tremelimumab was approved for unresectable hepatocellular carcinoma medical use in the United States in Oc ...
.
The 2018
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accord ...
was awarded to
James P. Allison
James Patrick Allison (born August 7, 1948) is an American immunologist and Nobel laureate who holds the position of professor and chair of immunology and executive director of immunotherapy platform at the MD Anderson Cancer Center at the Uni ...
and
Tasuku Honjo
is a Japanese physician-scientist and immunologist. He won the 2018 Nobel Prize in Physiology or Medicine and is best known for his identification of programmed cell death protein 1 (PD-1).
He is also known for his molecular identification o ...
"for their discovery of cancer therapy by inhibition of negative immune regulation".
Interactions
CTLA-4 has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
*
AP2M1
AP-2 complex subunit mu is a protein that in humans is encoded by the ''AP2M1'' gene.
Function
This gene encodes a subunit of the heterotetrameric coat assembly protein complex 2 (AP2), which belongs to the adaptor complexes medium subunits fa ...
,
*
CD80
The Cluster of differentiation 80 (also CD80 and B7-1) is a B7, type I membrane protein in the immunoglobulin superfamily, with an extracellular immunoglobulin constant-like domain and a variable-like domain required for receptor binding. It is cl ...
,
*
CD86
Cluster of Differentiation 86 (also known as CD86 and B7-2) is a protein constitutively expressed on dendritic cells, Langerhans cells, macrophages, B-cells (including memory B-cells), and on other antigen-presenting cells. Along with CD80, CD8 ...
,
*
SHP-2
Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in huma ...
, and
*
PPP2R5A
Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform is an enzyme that in humans is encoded by the ''PPP2R5A'' gene.
Function
The product of this gene belongs to the phosphatase 2A regulatory subunit B family. Protei ...
.
References
Further reading
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External links
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{{Use dmy dates, date=April 2017
Clusters of differentiation
T cells