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Existing genome-wide CRISPR screens in primary human T cells either profile the transcriptome or isolate cells based on a single functional or protein phenotype. Here we present SCITO-Perturb-seq, a novel platform that couples combinatorial-indexed single-cell cytometry sequencing with pooled CRISPR activation (CRISPRa) to map the causal regulation of 201 surface proteins across 3.6 million human CD4 T cells. We find that 16% of activated genes significantly alter the expression of at least one surface protein. By applying semi-nonnegative matrix factorization to the perturbation effect matrix, we identified five modules corresponding to known CD4 T cell states. Notably, these modules group surface proteins by their shared response to perturbation, revealing coordinated regulation of proteins that are not co-expressed in unperturbed cells. SCITO-Perturb-seq represents the first genome-wide CRISPRa screen paired with direct, high-dimensional surface protein profiling, providing a comprehensive regulatory map of the CD4 T cell surface proteome.<\/jats:p>","DOI":"10.64898\/2026.08.08.743670","type":"posted-content","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T17:55:16Z","timestamp":1786470916000},"source":"Crossref","is-referenced-by-count":0,"title":["A genome-wide CRISPR activation map of surface protein expression in human CD4 T cells"],"prefix":"10.64898","author":[{"given":"Yutong V.","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"},{"name":"Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junha","family":"Park","sequence":"additional","affiliation":[{"name":"Yonsei University College of 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