{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T13:43:19Z","timestamp":1750340599709,"version":"3.38.0"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2018,9,1]],"date-time":"2018-09-01T00:00:00Z","timestamp":1535760000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Fungal infections in CD4+ T cell immunocompromised patients have risen sharply in recent years. Although vaccines offer a rational avenue to prevent infections, there are no licensed fungal vaccines available. Inactivated vaccines are safer but less efficacious and require adjuvants that may undesirably bias toward poor protective immune responses. We hypothesized that reducing the TCR signaling threshold could potentiate antifungal CD8+ T cell responses and immunity to inactivated vaccine in the absence of CD4+ T cells. In this study, we show that CBLB, a negative regulator of TCR signaling, suppresses CD8+ T cells in response to inactivated fungal vaccination in a mouse model of CD4+ T cell lymphopenia. Conversely, Cblb deficiency enhanced both the type 1 (e.g., IFN-\u03b3) and type 17 (IL-17A) CD8+ T cell responses to inactivated fungal vaccines and augmented vaccine immunity to lethal fungal pneumonia. Furthermore, we show that immunization with live or inactivated vaccine yeast did not cause detectable pathologic condition in Cblb\u2212\/\u2212 mice. Augmented CD8+ T cell responses in the absence of CBLB also did not lead to terminal differentiation or adversely affect the expression of transcription factors T-bet, Eomes, and ROR\u03b3t. Additionally, our adoptive transfer experiments showed that CBLB impedes the effector CD8+ T cell responses in a cell-intrinsic manner. Finally, we showed that ablation of Cblb overcomes the requirement of HIF-1\u03b1 for expansion of CD8+ T cells upon vaccination. Thus, adjuvants that target CBLB may augment inactivated vaccines and immunity against systemic fungal infections in vulnerable patients.<\/jats:p>","DOI":"10.4049\/jimmunol.1701241","type":"journal-article","created":{"date-parts":[[2018,7,27]],"date-time":"2018-07-27T14:54:45Z","timestamp":1532703285000},"page":"1717-1726","source":"Crossref","is-referenced-by-count":13,"title":["CBLB Constrains Inactivated Vaccine\u2013Induced CD8+ T Cell Responses and Immunity against Lethal Fungal Pneumonia"],"prefix":"10.1093","volume":"201","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8022-1353","authenticated-orcid":false,"given":"Som G","family":"Nanjappa","sequence":"first","affiliation":[{"name":"Department of Pathobiology, University of Illinois at Urbana-Champaign , Urbana, IL 61802"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9775-2089","authenticated-orcid":false,"given":"Srinivasu","family":"Mudalagiriyappa","sequence":"additional","affiliation":[{"name":"Department of Pathobiology, University of Illinois at Urbana-Champaign , Urbana, IL 61802"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4294-730X","authenticated-orcid":false,"given":"J Scott","family":"Fites","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Wisconsin School of Medicine and Public Health , Madison, WI 53792"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Suresh","sequence":"additional","affiliation":[{"name":"Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin , Madison, WI 53706"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruce S","family":"Klein","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Wisconsin School of Medicine and Public Health , Madison, WI 53792"},{"name":"Department of Internal Medicine, University of Wisconsin School of Medicine and Public Health , Madison, WI 53792"},{"name":"Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health , Madison, WI 53792"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2018,9,15]]},"reference":[{"key":"2025030417572662900_r1","doi-asserted-by":"crossref","first-page":"165rv13","DOI":"10.1126\/scitranslmed.3004404","article-title":"Hidden killers: human fungal infections","volume":"4","author":"Brown","year":"2012","journal-title":"Sci. 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[Published erratum appears in 2014 PLoS Pathog. 10: e1004148.]","volume":"8","author":"Nanjappa","year":"2012","journal-title":"PLoS Pathog."},{"key":"2025030417572662900_r4","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1038\/icb.2010.155","article-title":"Insights into human CD8(+) T-cell memory using the yellow fever and smallpox vaccines","volume":"89","author":"Ahmed","year":"2011","journal-title":"Immunol. Cell Biol."},{"key":"2025030417572662900_r5","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1146\/annurev-immunol-030409-101212","article-title":"Differentiation of effector CD4 T cell populations (*)","volume":"28","author":"Zhu","year":"2010","journal-title":"Annu. Rev. Immunol."},{"key":"2025030417572662900_r6","doi-asserted-by":"crossref","first-page":"617","DOI":"10.3389\/fimmu.2015.00617","article-title":"TCR signaling in T cell memory","volume":"6","author":"Daniels","year":"2015","journal-title":"Front. 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