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Here, we analyzed a mouse model of the Cre-dependent functional inactivation of p110\u03b1 (kinase dead) in T lymphocytes (p110\u03b1KD-T, KD). KD mice showed increased cellularity in thymus and spleen and altered T cell differentiation with increased number of CD4+CD8+ DP thymocytes, enhanced proportion of CD4+ SP lymphocytes linked to altered apoptosis, lower Treg cells, and increased AKT and ERK phosphorylation in activated thymocytes. In the spleen, the percentages of CD4+ Treg cells and CD8+ naive lymphocytes were reduced. In vitro, the differentiation of CD4+ cells from p110\u03b1KD-T mice showed lower induced Treg (iTreg) cell yield or IL-10 secretion. Moreover, Tfh cell yield, IL-21 secretion, and PI3-K-dependent elongation were hampered, as was Erk and Akt activation. Th1 or Th17 differentiation in vitro was not altered. The immunization of p110\u03b1-KD-T mice with KLH protein antigen induced an enhanced proportion of CXCR5+ CD4+ cells and germinal center B cells, increased ICOS expression in CD4+ cells, or IFN-\u03b3 secretion upon antigen re-activation in vitro. However, anti-KLH antibody responses in serum was similar in WT or p110\u03b1 KD mice. These data show that T cell-specific p110\u03b1 inactivation alters T cell differentiation and function.<\/jats:p>","DOI":"10.3390\/ijms26020595","type":"journal-article","created":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T07:40:08Z","timestamp":1736754008000},"page":"595","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["T Cell-Specific Inactivation of the PI3K p110\u03b1 Catalytic Subunit: Effect in T Cell Differentiation and Antigen-Specific Responses"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4016-1848","authenticated-orcid":false,"given":"Alejandro C.","family":"Briones","sequence":"first","affiliation":[{"name":"Centro Nacional de Microbiolog\u00eda, Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain"},{"name":"Department of Immunology, Complutense University School of Medicine, i+12 Research Institute, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2773-8986","authenticated-orcid":false,"given":"Laura","family":"del Estal","sequence":"additional","affiliation":[{"name":"Centro Nacional de Microbiolog\u00eda, Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7520-1603","authenticated-orcid":false,"given":"Cristina","family":"Villa-G\u00f3mez","sequence":"additional","affiliation":[{"name":"Centro Nacional de Microbiolog\u00eda, Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ver\u00f3nica","family":"Bermejo","sequence":"additional","affiliation":[{"name":"Centro Nacional de Microbiolog\u00eda, Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9927-5052","authenticated-orcid":false,"given":"Isabel","family":"Cervera","sequence":"additional","affiliation":[{"name":"Centro Nacional de Microbiolog\u00eda, Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pedro","family":"Guti\u00e9rrez-Huerta","sequence":"additional","affiliation":[{"name":"Centro Nacional de Microbiolog\u00eda, Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda","family":"Montes-Casado","sequence":"additional","affiliation":[{"name":"Centro Nacional de Microbiolog\u00eda, Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sagrario","family":"Ortega","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Oncol\u00f3gicas (CNIO), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariano","family":"Barbacid","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Oncol\u00f3gicas (CNIO), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9032-0072","authenticated-orcid":false,"given":"Jos\u00e9 Mar\u00eda","family":"Rojo","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas Margarita Salas, Consejo Superior de Investigaciones Cient\u00edficas (CSIC), 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6973-0835","authenticated-orcid":false,"given":"Pilar","family":"Portol\u00e9s","sequence":"additional","affiliation":[{"name":"Centro Nacional de Microbiolog\u00eda, Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3237","DOI":"10.4049\/jimmunol.2000599","article-title":"A case for Phosphoinositide 3-Kinase\u2013targeted therapy for infectious disease","volume":"205","author":"Adefemi","year":"2020","journal-title":"J. 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