CD28 family receptor

Group of regulatory cell surface receptors

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]

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

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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

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### Cancer

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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

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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

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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]

## References

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1. ^ a b Arch RH, Green JM (2012). "Chapter 16: Costimulatory molecules in T-cell activation and transplantation: Section 2: The CD28 receptor family". In Burlingham WJ, Wilkes DS (eds.). Immunobiology of Organ Transplantation. Boston, MA: Springer US. pp. 292–8\. ISBN 978-1-4419-8999-4.
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. ^ a b 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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Immunoglobulin superfamily: CD28 family receptors

receptors|

* BTLA
* CD28
* CTLA-4
* ICOS
* PD-1

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