CD28 Gene Editing

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CD28 Gene Editing    

CD28 is a homodimeric stimulatory cell surface receptor of the Ig superfamily. It is expressed on virtually all T-cells in rodents, and on the vast majority of CD4+ but only about half of circulating human CD8+ T-cells. The control of T-cell responses by CD28 co-stimulation provides a way to prevent unwanted (anti-self) and triggering wanted (antimicrobial) immunity. CD28 drives key intracellular biochemical events including unique phosphorylation and transcriptional signaling, and the production of key chemokines, cytokines, and survival signals that are essential for long-term expansion and differentiation of T cells. Therefore, mice deficient in CD28 show a series of immune defects including impaired T cell activation, poor memory T cell responses, and a lack of T cell help for B cells. Importantly, treatment of mice with a soluble CD28 antagonist induced antigen-specific tolerance, thus preventing the progression of autoimmune diseases and organ graft rejection. On the contrary, the emergence of CD28 agonists, which can rescue T cells from the tolerant state, may pave the way for new immune activators for the treatment of infectious diseases and cancer.

CD28 Ligand Binding and Signaling Pathways

It is becoming increasingly clear that CD28 functions not simply as an amplifier of TCR signals but delivers unique signals that control intracellular biochemical events, from post-translational protein modification to epigenetic changes that alter the gene expression program of T cells. CD28 and CTLA4 are highly homologous, competing for the same ligands (B7-1 [CD80] and B7-2 [CD86]). CTLA4 binds these ligands with a higher affinity than CD28 does, which enables CTLA4 to compete with CD28 for ligands and suppress effector T cell responses. Although the combination of CTLA4 with CD80 or CD86 is always stronger than CD28 binding, when in competition, CD86 has a higher preference for CD28 than CD80, which binds very strongly to CTLA4. Therefore, the sequential expression of CD86 followed by CD80 on APCs could function to increase the suppressive function of CTLA4 once an immune response has started given that the CTLA4-CD80 interaction later in an immune response is particularly strong.

 Shared interactions between CD28 and CTLA-4 family members.Figure 1. Shared interactions between CD28 and CTLA-4 family members. (Gardner D, et al., 2014)

In general, CD28 induces a co-stimulatory signal in the T-cell upon co-ligation together with the TCR, thereby amplifying the TCR complex-derived signal and by recruiting additional signaling molecules. CTLA-4, a negative regulator, counteracts CD28 signaling in cis by recruiting inhibitory phosphatases to the IS, and in trans by transmitting inhibitory signals into APCs, as well as by competing for the binding and removing of co-stimulatory ligands.

Targeting CD28 Co-stimulatory Pathways

A large number of literatures have shown that, in mouse models, CD28 and CTLA4 are critical regulators of autoimmune disease and tolerance to solid organ transplants. Genome-wide association studies have found single nucleotide polymorphisms (SNPs) in CD28 and CTLA4 that increase the risk for autoimmune disease. Increased numbers of circulating oligoclonal CD4+CD28- T cells have been reported in autoinflammatory and autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. These cells can also be found infiltrating into tissue affected by autoimmune processes. CD4+CD28- cells are also elevated in diverse conditions including chronic kidney graft rejection, acute coronary syndrome, and cytomegalovirus infection.

The centrality of CD28 costimulatory signals in T cell function makes it a tempting target for drugs to modulate the function of both effector T cells and Treg cells. Ligand blockade is the most widely used method for manipulation of the CD28/CTLA-4 pathway. Blocking antibodies to CD80 and CD86 have been developed as a strategy to block the CD28/CTLA-4 pathway; however, although selective ligand blockade has some potential advantages for tailoring immune responses, it has not been widely applied in a clinical setting. Compared with the selective blockade of CD80 and CD86, simultaneous blockade of both ligands has been widely used in the fusion protein CTLA-4-Ig now available clinically in two forms: abatacept and belatacept. Studies have shown that Abatacept, similar to CTLA-4 itself, has a high affinity for CD80 and CD86, blocks CD28-dependent co-stimulation, and inhibits T-cell proliferation in vitro. Based on these results, CTLA-4-Ig was successfully detected in numerous preclinical animal models of autoimmune diseases.

CD28 Gene Editing Services

CRISPR/Cas9 PlatformCB at Creative Biogene is dedicated to offering comprehensive CRISPR/Cas9 gene editing services and products for academic research, biotech research and pharmaceutical drug discovery. With deep gene editing knowledge and extensive experience in experimental operation and data processing, we help you effectively control CD28 genes knockout/knockin/point mutation in cells or animals via CRISPR/Cas9 technology.

ServiceDetailsAlternative cell lines or animal species
CD28 Gene Editing Cell Line GenerationgRNA design and synthesis
Transfect the cell lines you're interested
Select the high expression cells and sort monoclonal cell
Validate the knockout/knockin/point mutation of CD28 by PCR and sequencing
Provide cryogenically preserved vials of stable cells and final reports
HEK239T, Hela, HepG2, U87, Ba/F3, CHO, MDA-MB-453, MDA-MB-231NIH3T3, T47D, Neuro2a, MCF7, RKO, K562, RAW264.7, etc.
CD28 Gene Editing Animal Model GenerationCD28 gene conventional knockout animals
CD28 gene conditional knockout animals
CD28 point mutation animals
CD28 knockin animals
Mouse, rat, rabbit, zebrafish, C. elegans, etc.

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References

  1. Beyersdorf N, et al. CD28 co-stimulation in T-cell homeostasis: a recent perspective. ImmunoTargets and therapy, 2015, 4: 111.
  2. Gardner D, et al. Understanding the CD28/CTLA-4 (CD152) pathway and its implications for costimulatory blockade. American Journal of Transplantation, 2014, 14(9): 1985-1991.
  3. Esensten J H, et al. CD28 costimulation: from mechanism to therapy. Immunity, 2016, 44(5): 973-988.
  4. Adams A B, et al. Costimulation blockade in autoimmunity and transplantation: the CD28 pathway. The Journal of Immunology, 2016, 197(6): 2045-2050.
  5. Mou D, et al. CD28 negative T cells: is their loss our gain?. American Journal of Transplantation, 2014, 14(11): 2460-2466.
For research use only. Not intended for any clinical use.

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