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Autologous T-APC cultures were obtained from small peripheral blood mononuclear cell samples that yielded over 1020-fold expansions by an approach that did not require cell purification or genetic manipulation. Primary T-APCs constitutively expressed major histocompatibility complex class II glycoproteins, costimulatory B7 molecules, and FOXP3 in long-term culture. Autologous expansion yielded both CD4+ and CD8+ T-APC subsets that expressed signature activation markers and rapid cell division over 1 to 2\u2009mo of culture in the absence of exogenous mitogenic or antigenic stimuli. Autologous IL-2\u2013driven expansion of CD4+ T-APCs required TCR engagement because continuous T cell proliferation was blocked by neutralizing monoclonal antibodies against CD4, and constitutive expression of CD40L was inhibited by neutralizing major histocompatibility complex class II monoclonal antibodies. Long-term expansion required continuous TGF-\u03b2 exposure, which increased HLA-DR and CD25 expression with consequent enhancement of antigen presentation, autologous TCR recognition, and IL-2 responsiveness. Low IL-2\/TGF-\u03b2 concentrations favored CD25high CD69low PD1low T-APC subsets, whereas high IL-2\/TGF-\u03b2 concentrations favored CD25low CD69high PD1high T-APC subsets. T-APC presentation of agonistic self-antigens induced extensive blastogenesis of polyclonal syngeneic responder T cells, some of which differentiated de novo into exponentially expanding T-APC lines. Overall, this study reveals professional T-APC subsets that exhibit exponential autologous expansion in vitro via autologous self-presentation and agonistic TCR self-recognition. These T-APCs may regulate homeostatic self-reactivity of the human TCR\u03b1\/\u03b2 repertoire and may mediate, in part, autologous mixed lymphocyte reactions.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag274","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T19:32:03Z","timestamp":1792611123000},"source":"Crossref","is-referenced-by-count":0,"title":["A human self-stimulatory CD4+ T cell antigen-presenting cell subset presents and recognizes agonistic self-antigens to sustain exponential autologous clonal expansion"],"prefix":"10.1093","volume":"215","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-1525-214X","authenticated-orcid":false,"given":"Christian K","family":"Smallwood","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University , Greenville, NC,","place":["United 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