CD28 family receptor

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The left image is a visual of CD28 attached to a T cell interacting in costimulation with B7 to activate the T cell and promote an immune response. Activation of T and B cells.png
The left image is a visual of CD28 attached to a T cell interacting in costimulation with B7 to activate the T cell and promote an immune response.

CD28 family receptors are a group of regulatory cell surface receptors expressed on immune cells. The CD28 family in turn is a subgroup of the immunoglobulin superfamily. [1]

Contents

Two family members, CD28 and ICOS, act as positive regulators of T cell function while another three, BTLA, [2] CTLA-4 and PD-1 act as inhibitors. [1] Ligands for the CD28 receptor family include B7 family proteins. [3]

CD28 receptors play a role in the development and proliferation of T cells. [4] The CD28 receptors enhance signals from the T cell receptors (TCR) in order to stimulate an immune response [5] and an anti-inflammatory response on regulatory T cells. Through the promotion of T cell function, CD28 receptors allow effector T cells to combat regulatory T cell-mediated suppression from adaptive immunity. CD28 receptors also elicit the prevention of spontaneous autoimmunity.

Function

CD28 receptors aid in other T cell processes such as cytoskeletal remodeling, production of cytokines and chemokines and intracellular biochemical reactions (i.e. phosphorylation, transcriptional signaling, and metabolism) that are key for T cell proliferation and differentiation. Ligation of CD28 receptors causes epigenetic, transcriptional and post-translational alterations in T cells. Specifically, CD28 costimulation controls many aspects within T cells, one being the expression of proinflammatory cytokine genes. A particular cytokine gene encodes for IL-2, which influences T cell proliferation, survival, and differentiation. The absence of CD28 costimulation results in the loss of IL-2 production causing the T cells to be anergic. [6] Additionally, CD28 ligation causes arginine-methylation for many proteins. CD28 also drives transcription within T cells and produce signals that lead to IL-2 production and Bcl-xL regulation, an antiapoptotic protein, which are essential for T cell survival. [7] CD28 receptors can be seen on 80% of human CD4+ and 50% of CD8+ T cells, in which this percentage decreases with age. [8]

Clinical significance

Cancer

Some cancer cells evade destruction by the immune system through an overexpression of B7 ligands that bind to inhibitory CD28 family member receptors on immune cells. [9] Antibodies directed against CD28 family members CTLA-4, PD-1, or their B7 ligands function as checkpoint inhibitors to overcome tumor immune tolerance and are clinically used in cancer immunotherapy. [9]

Additionally, genetically engineered T cells containing CD28 and CD137 can be used in a molecularly targeted therapy response to a type of carcinomas called mesothelin. These T cells have a high affinity for human mesothelin. Upon mesothelin stimulation, the T cells proliferate, express an antiapoptotic gene, and secrete cytokines with the help of CD28 expression. When introduced to mice with pre-existing tumors, these T cells remove the tumors completely. The CD137 presence within the cells maintains the persistence of the engineered T cells. This interaction between engineered T cells with CD28 and CD137 are essential for immunotherapy, and show promise for directing T lymphocytes to tumor antigens and altering the tumor microenvironment for mesothelin. [10]

HIV

The CD28 pathway is targeted by the human immunodeficiency virus (HIV) as the virus infects large numbers of normal cells. CD28 has effects on the transcription and stability of interleukin-2 and IFN-γ, cytokines that are important for immunity and stimulating NK cells. HIV alters the CD28 signaling as well as CD8 cells. As a result, there are reduced levels of CD8 cells, which express CD28, in individuals with HIV. With regards to subjects with both Hepatitis C Virus (HCV) and HIV, levels of CD8 cells are also reduced. CD28 signaling has a large role in the adaptive response to HCV and can increase morbidity for HCV/HIV coinfection within a subject. [11] CD28 induces IL-2 secretion that increases IL-2 mRNA stability. CD28 costimulation influences the expression of key genes expressed in T cell differentiation. Tat, a regulatory protein that regulates viral transcription, increases the transcription of the HIV dsDNA. CD28 costimulation with the Tat protein can contribute to chronic immune hyperactivation seen among HIV-infected individuals. Thus, CD28 is an essential part of therapeutics for the infection and pathogenesis of HIV. [12]

Hyper-induced inflammatory cytokines

Binding CD28 to superantigens can induce an overexpression of inflammatory cytokines which may be harmful. When CD28 interacts with coligand B7-2, these superantigens elicit T-cell hyperactivation. Superantigens can form this overexpression by controlling interactions between MHC-II and TCRs as well as increasing the B7-2 and CD28 costimulatory interactions. This is dangerous because the overexpression of inflammatory cytokines can cause toxic shock in an individual. [13]

Related Research Articles

<span class="mw-page-title-main">T helper cell</span> Type of immune 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 considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.

<span class="mw-page-title-main">Interleukin 10</span> Anti-inflammatory cytokine

Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. In humans, interleukin 10 is encoded by the IL10 gene. IL-10 signals through a receptor complex consisting of two IL-10 receptor-1 and two IL-10 receptor-2 proteins. Consequently, the functional receptor consists of four IL-10 receptor molecules. IL-10 binding induces STAT3 signalling via the phosphorylation of the cytoplasmic tails of IL-10 receptor 1 + IL-10 receptor 2 by JAK1 and Tyk2 respectively.

<span class="mw-page-title-main">Superantigen</span> Antigen which strongly activates the immune system

Superantigens (SAgs) are a class of antigens that result in excessive activation of the immune system. Specifically they cause non-specific activation of T-cells resulting in polyclonal T cell activation and massive cytokine release. SAgs are produced by some pathogenic viruses and bacteria most likely as a defense mechanism against the immune system. Compared to a normal antigen-induced T-cell response where 0.0001-0.001% of the body's T-cells are activated, these SAgs are capable of activating up to 20% of the body's T-cells. Furthermore, Anti-CD3 and Anti-CD28 antibodies (CD28-SuperMAB) have also shown to be highly potent superantigens.

<span class="mw-page-title-main">Interleukin 2</span> Mammalian protein found in Homo sapiens

Interleukin-2 (IL-2) is an interleukin, a type of cytokine signaling molecule in the immune system. It is a 15.5–16 kDa protein that regulates the activities of white blood cells (leukocytes, often lymphocytes) that are responsible for immunity. IL-2 is part of the body's natural response to microbial infection, and in discriminating between foreign ("non-self") and "self". IL-2 mediates its effects by binding to IL-2 receptors, which are expressed by lymphocytes. The major sources of IL-2 are activated CD4+ T cells and activated CD8+ T cells.

Alloimmunity is an immune response to nonself antigens from members of the same species, which are called alloantigens or isoantigens. Two major types of alloantigens are blood group antigens and histocompatibility antigens. In alloimmunity, the body creates antibodies against the alloantigens, attacking transfused blood, allotransplanted tissue, and even the fetus in some cases. Alloimmune (isoimmune) response results in graft rejection, which is manifested as deterioration or complete loss of graft function. In contrast, autoimmunity is an immune response to the self's own antigens. Alloimmunization (isoimmunization) is the process of becoming alloimmune, that is, developing the relevant antibodies for the first time.

<span class="mw-page-title-main">Interleukin 4</span> Mammalian protein found in Mus musculus

The interleukin 4 is a cytokine that induces differentiation of naive helper T cells (Th0 cells) to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4 in a positive feedback loop. IL-4 is produced primarily by mast cells, Th2 cells, eosinophils and basophils. It is closely related and has functions similar to IL-13.

<span class="mw-page-title-main">CD28</span> Mammalian protein found in humans

CD28 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 provide a potent signal for the production of various interleukins.

<span class="mw-page-title-main">Interleukin 19</span> Protein-coding gene in the species Homo sapiens

Interleukin 19 (IL-19) is an immunosuppressive protein that belongs to the IL-10 cytokine subfamily.

<span class="mw-page-title-main">CD80</span> Mammalian protein found in Homo sapiens

The Cluster of differentiation 80 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 closely related to CD86, another B7 protein (B7-2), and often works in tandem. Both CD80 and CD86 interact with costimulatory receptors CD28, CTLA-4 (CD152) and the p75 neurotrophin receptor.

<span class="mw-page-title-main">CD86</span> Mammalian protein found in Homo sapiens

Cluster of Differentiation 86 is a protein constitutively expressed on dendritic cells, Langerhans cells, macrophages, B-cells, and on other antigen-presenting cells. Along with CD80, CD86 provides costimulatory signals necessary for T cell activation and survival. Depending on the ligand bound, CD86 can signal for self-regulation and cell-cell association, or for attenuation of regulation and cell-cell disassociation.

<span class="mw-page-title-main">CD134</span> Protein-coding gene in humans

Tumor necrosis factor receptor superfamily, member 4 (TNFRSF4), also known as CD134 and OX40 receptor, is a member of the TNFR-superfamily of receptors which is not constitutively expressed on resting naïve T cells, unlike CD28. OX40 is a secondary co-stimulatory immune checkpoint molecule, expressed after 24 to 72 hours following activation; its ligand, OX40L, is also not expressed on resting antigen presenting cells, but is following their activation. Expression of OX40 is dependent on full activation of the T cell; without CD28, expression of OX40 is delayed and of fourfold lower levels.

<span class="mw-page-title-main">CD137</span> Member of the tumor necrosis factor (TNF) receptor family

CD137, a member of the tumor necrosis factor (TNF) receptor family, is a type 1 transmembrane protein, expressed on surfaces of leukocytes and non-immune cells. Its alternative names are tumor necrosis factor receptor superfamily member 9 (TNFRSF9), 4-1BB, and induced by lymphocyte activation (ILA). It is of interest to immunologists as a co-stimulatory immune checkpoint molecule, and as a potential target in cancer immunotherapy.

In immunology, peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in the immune periphery. Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease. Peripheral tolerance prevents immune response to harmless food antigens and allergens, too.

Interleukin 35 (IL-35) is a recently discovered anti-inflammatory cytokine from the IL-12 family. Member of IL-12 family - IL-35 is produced by wide range of regulatory lymphocytes and plays a role in immune suppression. IL-35 can block the development of Th1 and Th17 cells by limiting early T cell proliferation.

<span class="mw-page-title-main">Programmed cell death protein 1</span> Mammalian protein found in Homo sapiens

Programmed cell death protein 1, also known as PD-1 and CD279, is a protein on the surface of T and B cells that has a role in regulating the immune system's response to the cells of the human body by down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells.

<span class="mw-page-title-main">ICOSLG</span> Protein-coding gene in the species Homo sapiens

ICOS ligand is a protein that in humans is encoded by the ICOSLG gene located at chromosome 21. ICOSLG has also been designated as CD275.

<span class="mw-page-title-main">MARCO</span> Protein-coding gene in the species Homo sapiens

Macrophage receptor with collagenous structure (MARCO) is a protein that in humans is encoded by the MARCO gene. MARCO is a class A scavenger receptor that is found on particular subsets of macrophages. Scavenger receptors are pattern recognition receptors (PRRs) found most commonly on immune cells. Their defining feature is that they bind to polyanions and modified forms of a type of cholesterol called low-density lipoprotein (LDL). MARCO is able to bind and phagocytose these ligands and pathogen-associated molecular patterns (PAMPs), leading to the clearance of pathogens and cell signaling events that lead to inflammation. As part of the innate immune system, MARCO clears, or scavenges, pathogens, which leads to inflammatory responses. The scavenger receptor cysteine-rich (SRCR) domain at the end of the extracellular side of MARCO binds ligands to activate the subsequent immune responses. MARCO expression on macrophages has been associated with tumor development and also with Alzheimer's disease, via decreased responses of cells when ligands bind to MARCO.

<span class="mw-page-title-main">TNFRSF18</span> Protein-coding gene in the species Homo sapiens

Tumor necrosis factor receptor superfamily member 18 (TNFRSF18), also known as glucocorticoid-induced TNFR-related protein (GITR) or CD357. GITR is encoded and tnfrsf18 gene at chromosome 4 in mice. GITR is type I transmembrane protein and is described in 4 different isoforms. GITR human orthologue, also called activation-inducible TNFR family receptor (AITR), is encoded by the TNFRSF18 gene at chromosome 1.

<span class="mw-page-title-main">NKG2D</span> Protein-coding gene in the species Homo sapiens

NKG2D is an activating receptor (transmembrane protein) belonging to the NKG2 family of C-type lectin-like receptors. NKG2D is encoded by KLRK1 (killer cell lectin like receptor K1) gene which is located in the NK-gene complex (NKC) situated on chromosome 6 in mice and chromosome 12 in humans. In mice, it is expressed by NK cells, NK1.1+ T cells, γδ T cells, activated CD8+ αβ T cells and activated macrophages. In humans, it is expressed by NK cells, γδ T cells and CD8+ αβ T cells. NKG2D recognizes induced-self proteins from MIC and RAET1/ULBP families which appear on the surface of stressed, malignant transformed, and infected cells.

<span class="mw-page-title-main">Immune checkpoint</span> Regulators of the immune system

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 stimulating immune checkpoint targets.

References

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  2. ↑ Carreno BM, Collins M (October 2003). "BTLA: a new inhibitory receptor with a B7-like ligand". Trends in Immunology. 24 (10): 524–7. doi:10.1016/j.it.2003.08.005. PMID   14552835.
  3. ↑ Carreno BM, Collins M (2002). "The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses". Annual Review of Immunology. 20: 29–53. doi:10.1146/annurev.immunol.20.091101.091806. PMID   11861596.
  4. ↑ Wakamatsu E, Omori H, Ohtsuka S, Ogawa S, Green JM, Abe R (September 2018). "Regulatory T cell subsets are differentially dependent on CD28 for their proliferation". Molecular Immunology. 101: 92–101. doi:10.1016/j.molimm.2018.05.021. PMID   29909367. S2CID   49474303.
  5. ↑ Morin SO, Giroux V, Favre C, Bechah Y, Auphan-Anezin N, Roncagalli R, et al. (July 2015). "In the absence of its cytosolic domain, the CD28 molecule still contributes to T cell activation". Cellular and Molecular Life Sciences. 72 (14): 2739–48. doi:10.1007/s00018-015-1873-7. PMC   4826669 . PMID   25725801.
  6. ↑ Thomas RM, Gao L, Wells AD (April 2005). "Signals from CD28 induce stable epigenetic modification of the IL-2 promoter". Journal of Immunology. 174 (8): 4639–46. doi: 10.4049/jimmunol.174.8.4639 . PMID   15814687.
  7. ↑ Esensten JH, Helou YA, Chopra G, Weiss A, Bluestone JA (May 2016). "CD28 Costimulation: From Mechanism to Therapy". Immunity. 44 (5): 973–88. doi:10.1016/j.immuni.2016.04.020. PMC   4932896 . PMID   27192564.
  8. ↑ Esensten JH, Helou YA, Chopra G, Weiss A, Bluestone JA (May 2016). "CD28 Costimulation: From Mechanism to Therapy". Immunity. 44 (5): 973–88. doi:10.1016/j.immuni.2016.04.020. PMC   4932896 . PMID   27192564.
  9. 1 2 Leung J, Suh WK (December 2014). "The CD28-B7 Family in Anti-Tumor Immunity: Emerging Concepts in Cancer Immunotherapy". Immune Network. 14 (6): 265–76. doi:10.4110/in.2014.14.6.265. PMC   4275384 . PMID   25550693.
  10. ↑ Carpenito C, Milone MC, Hassan R, Simonet JC, Lakhal M, Suhoski MM, et al. (March 2009). "Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains". Proceedings of the National Academy of Sciences of the United States of America. 106 (9): 3360–5. Bibcode:2009PNAS..106.3360C. doi: 10.1073/pnas.0813101106 . PMC   2651342 . PMID   19211796.
  11. ↑ Yonkers NL, Rodriguez B, Post AB, Asaad R, Jones L, Lederman MM, et al. (August 2006). "HIV coinfection impairs CD28-mediated costimulation of hepatitis C virus-specific CD8 cells". The Journal of Infectious Diseases. 194 (3): 391–400. doi: 10.1086/505582 . PMID   16826489.
  12. ↑ Ott M, Emiliani S, Van Lint C, Herbein G, Lovett J, Chirmule N, et al. (March 1997). "Immune hyperactivation of HIV-1-infected T cells mediated by Tat and the CD28 pathway". Science. 275 (5305): 1481–5. doi:10.1126/science.275.5305.1481. PMID   9045614. S2CID   42857507.
  13. ↑ Levy R, Rotfogel Z, Hillman D, Popugailo A, Arad G, Supper E, et al. (October 2016). "Superantigens hyperinduce inflammatory cytokines by enhancing the B7-2/CD28 costimulatory receptor interaction". Proceedings of the National Academy of Sciences of the United States of America. 113 (42): E6437–E6446. Bibcode:2016PNAS..113E6437L. doi: 10.1073/pnas.1603321113 . PMC   5081635 . PMID   27708164.
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