Co-stimulation is a secondary signal which immune cells rely on to activate an
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 ...
in the presence of an
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. ...
-presenting cell.
In the case of T cells, two stimuli are required to fully activate their immune response. During the activation 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 ...
s, co-stimulation is often crucial to the development of an effective
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 ...
. Co-stimulation is required in addition to the antigen-specific signal from their antigen receptors.
T cell co-stimulation
T cells require two signals to become fully activated. A first signal, which is
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. ...
-specific, is provided through the
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) which interacts with peptide-
MHC molecules on the membrane of
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 ...
(APC). A second signal, the co-stimulatory signal, is antigen nonspecific and is provided by the interaction between co-stimulatory molecules expressed on the membrane of APC and the T cell.
One of the best characterized co-stimulatory molecules expressed by T cells is
CD28
CD28 (Cluster of Differentiation 28) is one of the proteins expressed on T cells that provide co-stimulatory signals required for T cell activation and survival. T cell stimulation through CD28 in addition to the T-cell receptor ( TCR) can provid ...
, which interacts with
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 ...
(B7.1) 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, CD ...
(B7.2) on the membrane of APC. Another costimulatory receptor expressed by T cells is
ICOS
Icos Corporation (trademark ICOS) was an American biotechnology company and the largest biotechnology company in the U.S. state of Washington, before it was sold to Eli Lilly and Company in 2007. It was founded in 1989 by David Blech, Isaac ...
( Inducible Costimulator), which interacts with ICOS-L.
T cell co-stimulation is necessary for T cell proliferation, differentiation and survival.
Activation of T cells without co-stimulation may lead to T cell
anergy
In immunology, anergy is a lack of reaction by the body's defense mechanisms to foreign substances, and consists of a direct induction of peripheral lymphocyte tolerance. An individual in a state of anergy often indicates that the immune system ...
, T cell deletion or the development of
immune 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 ...
.
B cell co-stimulation
B cell binds antigens with its BCR (a membrane-bound
antibody
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 ...
), which transfers intracellular signals to the B cell as well as inducing the B cell to engulf the antigen, process it, and present it on the MHC II molecules. The latter case induces recognition by antigen-specific
Th2 cells or Tfh cells, leading to activation of the B cell through binding of TCR to the MHC-antigen complex. It is followed by synthesis and presentation of
CD40L
CD154, also called CD40 ligand or CD40L, is a protein that is primarily expressed on activated T cells and is a member of the TNF superfamily of molecules. It binds to CD40 on antigen-presenting cells (APC), which leads to many effects depending ...
(CD154) on the Th2 cell, which binds to
CD40
Cluster of differentiation 40, CD40 is a costimulatory protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on T helper cell, TH cells to CD40 activates antigen presenting cells and induces a ...
on the B cell, thus the Th2 cell can co-stimulate the B cell.
[Janeway CA, Travers P, Walport M, Shlomchik M (2001). ''Immunobiology 5 : The Immune System in Health and Disease, 5th ed.'' New York: Garland Pub., ] Without this co-stimulation the B cell cannot proliferate further.
Co-stimulation for B cells is provided alternatively by
complement receptor
A complement receptor is a membrane-bound receptor belonging to the complement system, which is part of the innate immune system. Complement receptors bind effector protein fragments that are produced in response to antigen-antibody complexes ...
s. Microbes may activate the complement system directly and complement component
C3b
C3b is the larger of two elements formed by the cleavage of complement component 3, and is considered an important part of the innate immune system. C3b is potent in opsonization: tagging pathogens, immune complexes (antigen-antibody), and apopto ...
bind to microbes. After C3b is degraded into a fragment iC3b (inactive derivative of C3b), then cleaved to C3dg, and finally to C3d, which continue to bind to microbial surface, B cells express complement receptor
CR2 (CD21) to bind to iC3b, C3dg, or C3d.
[Frank K, Atkinson JP (2001). "Complement system." In Austen KF, Frank K, Atkinson JP, Cantor H. eds. ''Samter's Immunologic Diseases, 6th ed. Vol. 1,'' p. 281–298, Philadelphia: Lippincott Williams & Wilkins, ] This additional binding makes the B cells 100- to 10,000-fold more sensitive to antigen.
CR2 on mature B cells forms a complex with
CD19
B-lymphocyte antigen CD19, also known as CD19 molecule ( Cluster of Differentiation 19), B-Lymphocyte Surface Antigen B4, T-Cell Surface Antigen Leu-12 and CVID3 is a transmembrane protein that in humans is encoded by the gene ''CD19''. In humans, ...
and
CD81. This complex is called the B cell
coreceptor
A co-receptor is a cell surface receptor that binds a signalling molecule in addition to a primary receptor in order to facilitate ligand recognition and initiate biological processes, such as entry of a pathogen into a host cell.
Properties
The t ...
complex for such sensitivity enhancement to the antigen.
[Abbas AK, Lichtman AH (2003). ''Cellular and Molecular Immunology, 5th ed.'' Philadelphia: Saunders, .]
Applications
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 ...
(Orencia) is a T cell co-stimulation modulator approved for the treatment of
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 ...
. The
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 secreted by activated T cells are thought to both initiate and propagate the immunologically driven inflammation associated with rheumatoid arthritis. Orencia, a soluble
fusion protein
Fusion proteins or chimeric (kī-ˈmir-ik) proteins (literally, made of parts from different sources) are proteins created through the joining of two or more genes that originally coded for separate proteins. Translation of this ''fusion gene'' r ...
, works by altering the co-stimulatory signal required for full T-cell activation.
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 ...
is another novel molecule which is being tested as an
anti-rejection medication
Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are medication, drugs that inhibit or prevent activity of the immune system.
Classification
Immunosuppressive drugs can be cla ...
for use in renal transplantation.
A new co-stimulatory
superagonistic drug
A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...
,
TGN1412
Theralizumab (also known as TGN1412, CD28-SuperMAB, and TAB08) is an immunomodulatory drug developed by Thomas Hünig of the University of Würzburg. It was withdrawn from development after inducing severe inflammatory reactions as well as chroni ...
, was the subject of a
clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
at
Northwick Park Hospital
Northwick Park Hospital (NWPH) is a major National Health Service hospital situated near the town of Harrow, London, Harrow, North West London, managed by the London North West University Healthcare NHS Trust. It is located off Watford Road in th ...
,
London
London is the capital and largest city of England and the United Kingdom, with a population of just under 9 million. It stands on the River Thames in south-east England at the head of a estuary down to the North Sea, and has been a majo ...
. The trial became surrounded in controversy as the six volunteers became seriously ill within minutes of being given the drug.
In essence, the co-stimulatory molecules function as "flashing red lights" that interact with the T cell, communicating that the material being presented by the dendritic cell material indicates danger. Dendritic cells displaying co-stimulatory molecules while presenting antigen are able to activate T cells. In contrast, T cells that recognize antigen presented by a dendritic cell not displaying co-stimulatory molecules are generally driven to apoptosis, or may become unresponsive to future encounters with the antigen.
References
{{Reflist
Immunology