{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T04:46:41Z","timestamp":1768625201725,"version":"3.49.0"},"reference-count":113,"publisher":"American Society for Microbiology","issue":"17","license":[{"start":{"date-parts":[[2014,9,1]],"date-time":"2014-09-01T00:00:00Z","timestamp":1409529600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2014,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>The factors that determine CD4<jats:sup>+<\/jats:sup>T cell (T<jats:sub>CD4<jats:sup>+<\/jats:sup><\/jats:sub>) specificities, functional capacity, and memory persistence in response to complex pathogens remain unclear. We explored these parameters in the C57BL\/6 mouse through comparison of two highly related (&gt;92% homology) poxviruses: ectromelia virus (ECTV), a natural mouse pathogen, and vaccinia virus (VACV), a heterologous virus that nevertheless elicits potent immune responses. In addition to elucidating several previously unidentified major histocompatibility complex class II (MHC-II)-restricted epitopes, we observed many qualitative and quantitative differences between the T<jats:sub>CD4<jats:sup>+<\/jats:sup><\/jats:sub>repertoires, including responses not elicited by VACV despite complete sequence conservation. In addition, we observed functional heterogeneity between ECTV- and VACV-specific T<jats:sub>CD4<jats:sup>+<\/jats:sup><\/jats:sub>at both a global and individual epitope level, particularly greater expression of the cytolytic marker CD107a from T<jats:sub>CD4<jats:sup>+<\/jats:sup><\/jats:sub>following ECTV infection. Most striking were differences during the late memory phase where, in contrast to ECTV, VACV infection failed to elicit measurable epitope-specific T<jats:sub>CD4<jats:sup>+<\/jats:sup><\/jats:sub>as determined by intracellular cytokine staining. These findings illustrate the strong influence of epitope-extrinsic factors on T<jats:sub>CD4<jats:sup>+<\/jats:sup><\/jats:sub>responses and memory.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>Much of our understanding concerning host-pathogen relationships in the context of poxvirus infections stems from studies of VACV in mice. However, VACV is not a natural mouse pathogen, and therefore, the relevance of results obtained using this model may be limited. Here, we explored the MHC class II-restricted T<jats:sub>CD4<jats:sup>+<\/jats:sup><\/jats:sub>repertoire induced by mousepox (ECTV) infection and the functional profile of the responding epitope-specific T<jats:sub>CD4<jats:sup>+<\/jats:sup><\/jats:sub>, comparing these results to those induced by VACV infection under matched conditions. Despite a high degree of homology between the two viruses, we observed distinct specificity and functional profiles of T<jats:sub>CD4<jats:sup>+<\/jats:sup><\/jats:sub>responses at both acute and memory time points, with VACV-specific T<jats:sub>CD4<jats:sup>+<\/jats:sup><\/jats:sub>memory being notably compromised. These data offer insight into the impact of epitope-extrinsic factors on the resulting T<jats:sub>CD4<jats:sup>+<\/jats:sup><\/jats:sub>responses.<\/jats:p>","DOI":"10.1128\/jvi.01150-14","type":"journal-article","created":{"date-parts":[[2014,6,26]],"date-time":"2014-06-26T01:59:55Z","timestamp":1403747995000},"page":"10078-10091","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":15,"title":["Impact of Distinct Poxvirus Infections on the Specificities and Functionalities of CD4<sup>+<\/sup>T Cell Responses"],"prefix":"10.1128","volume":"88","author":[{"given":"Nicholas A.","family":"Siciliano","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam R.","family":"Hersperger","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA"},{"name":"Department of Biology, Albright College, Reading, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aimee M.","family":"Lacuanan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ren-Huan","family":"Xu","sequence":"additional","affiliation":[{"name":"Fox Chase Cancer Center, Immune Cell Development and Host Defense Program, Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Sidney","sequence":"additional","affiliation":[{"name":"Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Sette","sequence":"additional","affiliation":[{"name":"Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis J.","family":"Sigal","sequence":"additional","affiliation":[{"name":"Fox Chase Cancer Center, Immune Cell Development and Host Defense Program, Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurence C.","family":"Eisenlohr","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01441"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08511"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1202523"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01318"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1592"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-05-078154"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/jmcb\/mjp001"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3003165"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1202143109"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8235651"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1177\/0897190012456366"},{"key":"e_1_3_2_13_2","first-page":"547","article-title":"US military smallpox vaccination program: occupational impact of immunizations on aircrew in Air Mobility Command, US Air Force","volume":"107","author":"Folio LR","year":"2007","unstructured":"FolioLRYaoEF. 2007. 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