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Molecular and Functional Analyses of the Primordial Costimulatory Molecule CD80/86 and Its Receptors CD28 and CD152 (CTLA-4) in a Teleost Fish.

ABSTRACT: The moderate activation of T cells in mammals requires the costimulatory molecules, CD80 and CD86, on antigen-presenting cells to interact with their respective T cell receptors, CD28 and CD152 (CTLA-4), to promote costimulatory signals. In contrast, teleost fish (except salmonids) only possess CD80/86 as their sole primordial costimulatory molecule. However, the mechanism, which underlies the interaction between CD80/86 and its receptors CD28 and CD152 still requires elucidation. In this study, we cloned and identified the CD80/86, CD28, and CD152 genes of the grass carp (Ctenopharyngodon idella). The mRNA expression analysis showed that CD80/86, CD28, and CD152 were constitutively expressed in various tissues. Further analysis revealed that CD80/86 was highly expressed in IgM⁺ B cells. Conversely, CD28 and CD152 were highly expressed in CD4⁺ and CD8⁺ T cells. Subcellular localization illustrated that CD80/86, CD28, and CD152 are all located on the cell membrane. A yeast two-hybrid assay exhibited that CD80/86 can bind with both CD28 and CD152. In vivo assay showed that the expression of CD80/86 was rapidly upregulated in Aeromonas hydrophila infected fish compared to the control fish. However, the expression of CD28 and CD152 presented the inverse trend, suggesting that teleost fish may regulate T cell activation through the differential expression of CD28 and CD152. Importantly, we discovered that T cells were more likely to be activated by A. hydrophila after CD152 was blocked by anti-CD152 antibodies. This suggests that the teleost CD152 is an inhibitory receptor of T cell activation, which is similar to the mammalian CD152. Overall, this study begins to define the interaction feature between primordial CD80/86 and its receptors CD28 and CD152 in teleost fish, alongside providing a cross-species understanding of the evolution of the costimulatory signals throughout vertebrates.

SUBMITTER: Lu TZ

PROVIDER: S-EPMC9245511 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Rheumatoid arthritis (RA) is related to several pivotal susceptibility genes, including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and costimulatory molecule (CD80/CD86) genes. Although the connection between polymorphisms of CTLA-4 and CD86 genes in different populations of RA have been studied extensively, the results are controversial. Objective: To clarify the correlation in the Chinese Han population between CTLA-4, CD80/86, and CD28 gene polymorphisms, and RA susceptibility. Methods: A case-control study (574 RA patients and 804 controls) was conducted to determine the correlation between CTLA-4 rs231775 and rs16840252 gene polymorphisms, CD86 rs17281995 gene polymorphisms, and the risk of RA for the Chinese Han population. Furthermore, an additional meta-analysis, including three single nucleotide polymorphisms (SNPs) (CTLA-4 rs231775, CTLA-4 rs3087243, and CTLA-4 rs5742909) from 32 citations, including 43 studies, 24,703 cases and 23,825 controls was performed to elucidate the relationship between known SNPs in the CTLA-4 genes and RA for more robust conclusions. Results: The results showed that CTLA-4 rs231775 gene polymorphism decreased the RA risk (GA vs. AA, OR = 0.77, P = 0.025), whereas CTLA-4 rs16840252 and CD86 rs17281995 gene polymorphisms were not related to RA susceptibility. Stratification analyses by RF, ACPA, CRP, ESR, DAS28, and functional class identified significant associations for CTLA-4 rs231775 and rs16840252 gene polymorphisms in the RF-positive and RF-negative groups. A meta-analysis of the literature on CTLA-4 gene polymorphisms and RA risk revealed that the risk of RA was decreased by CTLA-4 rs231775 gene polymorphisms. Conclusions: The CTLA-4 rs231775 gene polymorphism decreased the risk of RA, whereas CTLA-4 rs16840252 and CD86 rs17281995 gene polymorphisms were not related to RA risk. A meta-analysis indicated that CTLA-4 rs231775 and rs3087243 gene polymorphisms decreased the risk of RA. To support these analytical results, additional clinical cases should be investigated in further studies.

Project description:Adoptive transfer of alloantigen-specific immunomodulatory cells generated ex vivo with anti-CD80/CD86 mAbs (2D10.4/IT2.2) holds promise for operational tolerance after transplantation. However, good manufacturing practice is required to allow widespread clinical application. Belatacept, a clinically approved cytotoxic T-lymphocyte antigen 4-immunoglobulin that also binds CD80/CD86, could be an alternative agent for 2D10.4/IT2.2. With the goal of generating an optimal cell treatment with clinically approved reagents, we evaluated the donor-specific immunomodulatory effects of belatacept- and 2D10.4/IT2.2-generated immunomodulatory cells. Immunomodulatory cells were generated by coculturing responder human peripheral blood mononuclear cells (PBMCs) (50 × 106 cells) with irradiated donor PBMCs (20 × 106 cells) from eight human leukocyte antigen-mismatched responder-donor pairs in the presence of either 2D10.4/IT2.2 (3 ?g/106 cells) or belatacept (40 ?g/106 cells). After 14 days of coculture, the frequencies of CD4+ T cells, CD8+ T cells, and natural killer cells as well as interferon gamma (IFN-?) production in the 2D10.4/IT2.2- and belatacept-treated groups were lower than those in the control group. The percentage of CD19+ B cells was higher in the 2D10.4/IT2.2- and belatacept-treated groups than in the control group. The frequency of CD4+CD25+CD127lowFOXP3+ T cells increased from 4.1±1.0% (preculture) to 7.1±2.6% and 7.3±2.6% (day 14) in the 2D10.4/IT2.2- and belatacept-treated groups, respectively (p<0.05). Concurrently, delta-2 FOXP3 mRNA expression increased significantly. Compared with cells derived from the no-antibody treated control group, cells generated from both the 2D10.4/IT2.2- and belatacept-treated groups produced lower IFN-? and higher interleukin-10 levels in response to donor-antigens, as detected by enzyme-linked immunospot. Most importantly, 2D10.4/IT2.2- and belatacept-generated cells effectively impeded the proliferative responses of freshly isolated responder PBMCs against donor-antigens. Our results indicate that belatacept-generated donor-specific immunomodulatory cells possess comparable phenotypes and immunomodulatory efficacies to those generated with 2D10.4/IT2.2. We suggest that belatacept could be used for ex vivo generation of clinical grade alloantigen-specific immunomodulatory cells for tolerance induction after transplantation.

Dataset Information

Molecular and Functional Analyses of the Primordial Costimulatory Molecule CD80/86 and Its Receptors CD28 and CD152 (CTLA-4) in a Teleost Fish.

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