AUTHOR=Lu Tao-Zhen , Liu Xun , Wu Chang-Song , Ma Zi-You , Wang Yang , Zhang Yong-An , Zhang Xu-Jie 

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

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.885005

DOI=10.3389/fimmu.2022.885005

ISSN=1664-3224

ABSTRACT=<p>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 <italic>CD80/86</italic>, <italic>CD28</italic>, and <italic>CD152</italic> genes of the grass carp (<italic>Ctenopharyngodon idella</italic>). The mRNA expression analysis showed that <italic>CD80/86</italic>, <italic>CD28</italic>, and <italic>CD152</italic> were constitutively expressed in various tissues. Further analysis revealed that <italic>CD80/86</italic> was highly expressed in IgM<sup>+</sup> B cells. Conversely, <italic>CD28</italic> and <italic>CD152</italic> were highly expressed in CD4<sup>+</sup> and CD8<sup>+</sup> 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. <italic>In vivo</italic> assay showed that the expression of <italic>CD80/86</italic> was rapidly upregulated in <italic>Aeromonas hydrophila</italic> infected fish compared to the control fish. However, the expression of <italic>CD28</italic> and <italic>CD152</italic> 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 <italic>A. hydrophila</italic> 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.</p>