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However, with respect to the activity of costimulatory and associated regulatory pathways, LCMV-specific T cell responses have long been regarded as relatively independent and thus distinct from the regulation of T cell immunity directed against many other viral pathogens. Here, we have reevaluated the contribution of CD28-CD80\/86 costimulation in the LCMV system by use of CD80\/86-deficient mice, and our results demonstrate that a disruption of CD28-CD80\/86 signaling compromises the magnitude, phenotype, and\/or functionality of LCMV-specific CD8<jats:sup>+<\/jats:sup>and\/or CD4<jats:sup>+<\/jats:sup>T cell populations in all stages of the T cell response. Notably, a profound inhibition of secondary T cell immunity in LCMV-immune CD80\/86-deficient mice emerged as a composite of both defective memory T cell development and a specific requirement for CD80 but not CD86 in the recall response, while a related experimental scenario of CD28-dependent yet CD80\/86-independent secondary CD8<jats:sup>+<\/jats:sup>T cell immunity suggests the existence of a CD28 ligand other than CD80\/86. Furthermore, we provide evidence that regulatory T cells (T<jats:sub>REG<\/jats:sub>s), the homeostasis of which is altered in CD80\/86<jats:sup>\u2212\/\u2212<\/jats:sup>mice, contribute to restrained LCMV-specific CD8<jats:sup>+<\/jats:sup>T cell responses in the presence of CD80\/86. Our observations can therefore provide a more coherent perspective on CD28-CD80\/86 costimulation in antiviral T cell immunity that positions the LCMV system within a shared context of multiple defects that virus-specific T cells acquire in the absence of CD28-CD80\/86 costimulation.<\/jats:p>","DOI":"10.1128\/jvi.05949-11","type":"journal-article","created":{"date-parts":[[2011,12,8]],"date-time":"2011-12-08T05:10:07Z","timestamp":1323321007000},"page":"1955-1970","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":33,"title":["Multiple Layers of CD80\/86-Dependent Costimulatory Activity Regulate Primary, Memory, and Secondary Lymphocytic Choriomeningitis Virus-Specific T Cell Immunity"],"prefix":"10.1128","volume":"86","author":[{"given":"Jens","family":"Eberlein","sequence":"first","affiliation":[{"name":"Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado, USA"},{"name":"Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado, USA"},{"name":"Integrated Department of Immunology, University of Colorado Denver, and National Jewish Health, Denver, Colorado, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bennett","family":"Davenport","sequence":"additional","affiliation":[{"name":"Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado, USA"},{"name":"Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado, USA"},{"name":"Integrated Department of Immunology, University of Colorado Denver, and National Jewish Health, Denver, Colorado, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom T.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado, USA"},{"name":"Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francisco","family":"Victorino","sequence":"additional","affiliation":[{"name":"Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado, USA"},{"name":"Integrated Department of Immunology, University of Colorado Denver, and National Jewish Health, Denver, Colorado, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tim","family":"Sparwasser","sequence":"additional","affiliation":[{"name":"Institute for Infection Immunology\/TWINCORE-Center for Experimental and Clinical Infection Research, Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirk","family":"Homann","sequence":"additional","affiliation":[{"name":"Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado, USA"},{"name":"Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado, USA"},{"name":"Integrated Department of Immunology, University of Colorado Denver, and National Jewish Health, Denver, Colorado, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.164.7.3689"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01839-10"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1003231"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2007.04.013"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.2.981"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2004.02.006"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.8.3777"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/1521-4141(200212)32:12<3376::AID-IMMU3376>3.0.CO;2-Y"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2009.02.005"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.10.6494"},{"key":"e_1_3_2_12_2","first-page":"593","volume-title":"Viral pathogenesis","author":"Borrow P","year":"1997","unstructured":"BorrowP OldstoneMBA. 1997. 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