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Transcriptome analysis of highly purified CD8+ cytomegalovirus (CMV)\u2013specific memory T cells after delivering defined antigen-specific TCR signals alone or with co-stimulatory signals revealed that the combination of TCR signaling and CD28 or 4-1BB co-stimulatory signals significantly altered the transcriptome compared to activation by TCR signaling alone. Nevertheless, IST-delivered CMV-specific or HIV-specific TCR signaling alone in the presence of IL-2 was sufficient to induce robust recall activation and expansion of CMV (NLV)\u2013specific or HIV (SL9)\u2013specific memory CD8+ T cells, respectively. This response contrasts with na\u00efve antigen-specific CD8+ T cells and TCR-engineered T cells, which required CD28 co-stimulation in addition to TCR stimulation for robust antigen-specific activation and expansion. These results have important implications by indicating that immunotherapeutics that deliver antigen-specific TCR signals alone in the presence of adequate environmental cytokine support should be sufficient for immune-based strategies designed to expand antigen-specific memory CD8+ T cells to eliminate cancerous or infected cells. In contrast, strategies that aim to optimally stimulate and expand virus or cancer-specific na\u00efve or TCR-engineered T-cell responses would benefit from the codelivery of TCR and CD28 signals.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf329","type":"journal-article","created":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T17:13:44Z","timestamp":1772385224000},"source":"Crossref","is-referenced-by-count":1,"title":["HIV- and cytomegalovirus-specific human memory CD8+ T cells are activated and expanded independent of co-stimulatory signaling by T-cell receptor\u2013specific immunotherapeutics"],"prefix":"10.1093","volume":"215","author":[{"given":"Christopher","family":"Hiner","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Albert Einstein College of Medicine , Bronx, NY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"April","family":"Mueller","sequence":"additional","affiliation":[{"name":"Department of 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