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Homeodomain-only protein (HOPX) negatively regulates CD8+ T cell proliferation and affects differentiation and aging

ABSTRACT: HOPX is an atypical homeodomain-containing protein lacking DNA-binding capacity. Via interaction with transcription factors, particularly SRF, it has critical functions in the development of various tissues. Here we unveil an essential regulatory role of HOPX in human T lymphocytes. Human CD8+ T cells expressed all three isoforms (a, b, and c) of HOPX wherein HOPXb was the predominant one. HOPX expression was induced by TCR activation and increased from TN to TEM cells. Overexpression of HOPX constrained the proliferation of TN cells while knockdown of HOPX promoted the proliferation of TEM cells upon TCR activation. Mechanistically, HOPX/SRF bound to the promoters and repressed expression of MYC and NR4A1, the key regulators of T cell proliferation and activation. Importantly, CD8+ T cells from the elderly had elevated levels of HOPX, correlated with their blunted TCR-induced proliferation. Knockdown of HOPX rescued the proliferative capacity of T cells from the elderly. Our results support that HOPX is a molecular switch that balances CD8+ T cell proliferation across subsets and with age.

ORGANISM(S): Homo sapiens

PROVIDER: GSE234697 | GEO | 2024/01/23

REPOSITORIES: GEO

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Project description:Purpose: Construction of a SARSCoV2 vaccine TCR specific machine learning model using single-cell TCR technology sequencing Methods：PBMCs were isolated from peripheral venous blood of HLA-A2+ healthy donors. PBMCs were incubated with antibody cocktail and then RapidSpheres, then the magnet was applied and unbound CD8+ T cells were recovered from the supernatant. According to the above method of CD8+ T activation, CD8+ T cells specific for ancestral epitopes were obtained by stimulating with the corresponding mutant ancestral peptides. Activation-specific CD8+ T cells were labeled with tetramers-PE and CD8-APC and then sorted out by flow cytometer FACS Canto (BD). The following protocol describes surface protein staining with hashtag antibodies for protein detection outside of the single cell V(D)J signature barcoding technique for differentiating CD8+ T cells with different epitope specificities after mixing up samples. The following is the hashtag information corresponding to the ancestral epitopes of the mutant strains. B.1.1.7 corresponds to the ancestral epitope ORF1a 1707-16 , ORF1a 2225-34 , ORF1a 2230-38. B.1.617.2 corresponds to the ancestral epitope M 82-90 . B.1.617.3 corresponds to the ancestral epitope ORF1a 2240-49, ORF1a 3683-92 , and ancestral epitope S 2-11 of B.1.526.2 without labeled hashtag protein. Cell number and viability were checked after surface protein hashtag staining (cell viability > 80%). Then droplet-encapsulation single-cell sequencing experiments were performed, and 10,000 living single cells were loaded onto each of the Chromium Controller (10x Genomics). After droplet-encapsulation, single-cell cDNA synthesis, amplification and sequencing libraries were generated using Chromium Single Cell 5' Feature Barcode Library Kit (10x Genomics),Chromium The result showed the inactivated vaccine is less protective in older adults, who take longer to develop effective antibodies, and the TCR diversity of each epitope specific repertoire decreased in the elderly. In addition, we found inactivated vaccines could stimulate the proliferation of related B cells in the body, thereby reducing the diversity of BCR in the body. Compared with the young, the elderly is less likely to produce antibody related BCR clones and the same is true for TCR diversity. Conclusions: The result showed the inactivated vaccine is less protective in older adults, who take longer to develop effective antibodies, and the TCR diversity of each epitope specific repertoire decreased in the elderly. In addition, we found inactivated vaccines could stimulate the proliferation of related B cells in the body, thereby reducing the diversity of BCR in the body. Compared with the young, the elderly is less likely to produce antibody related BCR clones and the same is true for TCR diversity.

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Homeodomain-only protein (HOPX) negatively regulates CD8+ T cell proliferation and affects differentiation and aging

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