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As the initial events that control T-cell activation in paracoccidioidomycosis (PCM) are not well established, we decided to investigate the role of CD28, an important costimulatory molecule for the activation of effector and regulatory T cells, in the immunity against this pulmonary pathogen. Using CD28-deficient (CD28<jats:sup>\u2212<\/jats:sup><jats:sup>\/<\/jats:sup><jats:sup>\u2212<\/jats:sup>) and normal wild-type (WT) C57BL\/6 mice, we were able to demonstrate that CD28 costimulation determines in pulmonary paracoccidioidomycosis an early immunoprotection but a late deleterious effect associated with impaired immunity and uncontrolled fungal growth. Up to week 10 postinfection, CD28<jats:sup>\u2212<\/jats:sup><jats:sup>\/<\/jats:sup><jats:sup>\u2212<\/jats:sup>mice presented increased pulmonary and hepatic fungal loads allied with diminished production of antibodies and pro- and anti-inflammatory cytokines besides impaired activation and migration of effector and regulatory T (Treg) cells to the lungs. Unexpectedly, CD28-sufficient mice progressively lost the control of fungal growth, resulting in an increased mortality associated with persistent presence of Treg cells, deactivation of inflammatory macrophages and T cells, prevalent presence of anti-inflammatory cytokines, elevated fungal burdens, and extensive hepatic lesions. As a whole, our findings suggest that CD28 is required for the early protective T-cell responses to<jats:italic>P. brasiliensis<\/jats:italic>infection, but it also induces the expansion of regulatory circuits that lately impair adaptive immunity, allowing uncontrolled fungal growth and overwhelming infection, which leads to precocious mortality of mice.<\/jats:p>","DOI":"10.1128\/iai.00297-10","type":"journal-article","created":{"date-parts":[[2010,8,17]],"date-time":"2010-08-17T01:46:50Z","timestamp":1282009610000},"page":"4922-4935","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":11,"title":["CD28 Exerts Protective and Detrimental Effects in a Pulmonary Model of Paracoccidioidomycosis"],"prefix":"10.1128","volume":"78","author":[{"given":"Mai\u0301ra","family":"Felonato","sequence":"first","affiliation":[{"name":"Departmento de Immunologia, Instituto de Cie\u0302ncias Biome\u0301dicas, Universidade de Sa\u0303o Paulo, Sa\u0303o Paulo, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adriana","family":"Pina","sequence":"additional","affiliation":[{"name":"Departmento de Immunologia, Instituto de Cie\u0302ncias Biome\u0301dicas, Universidade de Sa\u0303o Paulo, Sa\u0303o Paulo, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simone","family":"Bernardino","sequence":"additional","affiliation":[{"name":"Departmento de Immunologia, Instituto de Cie\u0302ncias Biome\u0301dicas, Universidade de Sa\u0303o Paulo, Sa\u0303o Paulo, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fla\u0301vio V.","family":"Loures","sequence":"additional","affiliation":[{"name":"Departmento de Immunologia, Instituto de Cie\u0302ncias Biome\u0301dicas, Universidade de Sa\u0303o Paulo, Sa\u0303o Paulo, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eliseu Frank","family":"de Araujo","sequence":"additional","affiliation":[{"name":"Departmento de Immunologia, Instituto de Cie\u0302ncias Biome\u0301dicas, Universidade de Sa\u0303o Paulo, Sa\u0303o Paulo, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vera L. 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