{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T23:34:57Z","timestamp":1790552097537,"version":"4.1.0"},"reference-count":50,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2014,10,21]],"date-time":"2014-10-21T00:00:00Z","timestamp":1413849600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/3.0\/"},{"start":{"date-parts":[[2014,10,31]],"date-time":"2014-10-31T00:00:00Z","timestamp":1414713600000},"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":["mBio"],"published-print":{"date-parts":[[2014,10,31]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The cytokine gamma interferon (IFN-\u03b3), with antimicrobial and immunoregulatory functions, can be produced by T cells following stimulation through their T cell receptors (TCRs) for antigen. The innate cytokines type 1 IFNs and interleukin-12 (IL-12) can also stimulate IFN-\u03b3 production by natural killer (NK) but not naive T cells. High basal expression of signal transducer and activator of transcription 4 (STAT4), used by type 1 IFN and IL-12 to induce IFN-\u03b3 as well as CD25, contributes to the NK cell responses. During acute viral infections, antigen-specific CD8 T cells are stimulated to express elevated STAT4 and respond to the innate factors with IFN-\u03b3 production. Little is known about the requirements for cytokine compared to TCR stimulation. Primary infections of mice with lymphocytic choriomeningitis virus (LCMV) demonstrated that although the elicited antigen-specific CD8 T cells acquired STAT4-dependent innate cytokine responsiveness for IFN-\u03b3 and CD25 induction\n                    <jats:italic>ex vivo<\/jats:italic>\n                    , TCR stimulation induced these through STAT4-independent pathways. During secondary infections, LCMV-immune CD8 T cells had STAT4-dependent IFN-\u03b3 expression at times of innate cytokine induction but subsequently expanded through STAT4-independent pathways. At times of innate cytokine responses during infection with the antigen-distinct murine cytomegalovirus virus (MCMV), NK and LCMV-immune CD8 T cells both had activation of pSTAT4 and IFN-\u03b3. The T cell IFN-\u03b3 response was STAT4 and IL-12 dependent, but antigen-dependent expansion was absent. By dissecting requirements for STAT4 and antigen, this work provides novel insights into the endogenous regulation of cytokine and proliferative responses and demonstrates conditioning of innate immunity by experience.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE<\/jats:bold>\n                    Understanding the regulation and function of adaptive immunity is key to the development of new and improved vaccines. Its CD8 T cells are activated through antigen-specific receptors to contribute to long-lasting immunity after natural infections or purposeful immunization. The antigen-receptor pathway of stimulation can lead to production of gamma interferon (IFN-\u03b3), a cytokine having both direct antimicrobial and immunoregulatory functions. Natural killer cells can also produce IFN-\u03b3 in response to the innate cytokines type 1 IFNs and\/or interleukin-12. This work demonstrates that CD8 T cells acquire parallel responsiveness to innate cytokine signaling for IFN-\u03b3 expression during their selection and development and maintain this capability to participate in innate immune responses as long-lived memory cells. Thus, CD8 T cells are conditioned to play a role in innate immunity, and their presence under immune conditions has the potential to regulate resistance to either secondary challenges or primary infections with unrelated agents.\n                  <\/jats:p>","DOI":"10.1128\/mbio.01978-14","type":"journal-article","created":{"date-parts":[[2014,10,22]],"date-time":"2014-10-22T02:14:11Z","timestamp":1413944051000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":32,"title":["CD8 T Cells in Innate Immune Responses: Using STAT4-Dependent but Antigen-Independent Pathways to Gamma Interferon during Viral Infection"],"prefix":"10.1128","volume":"5","author":[{"given":"Jenny E.","family":"Suarez-Ramirez","sequence":"first","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margarite L.","family":"Tarrio","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwangsin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delia A.","family":"Demers","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine A.","family":"Biron","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/0952-7915(95)80093-X"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.15.1.749"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI9232"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.03.026"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1201679"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1074900"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20070401"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00169-11"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/382174a0"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1201528"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-05-428672"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.189.8.1355"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.10.5827"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1203543109"},{"key":"e_1_3_3_16_2","doi-asserted-by":"crossref","first-page":"5238","DOI":"10.4049\/jimmunol.162.9.5238","article-title":"Synergism for cytokine-mediated disease during concurrent endotoxin and viral challenges: roles for NK and T cell IFN-gamma production","volume":"162","author":"Nguyen KB","year":"1999","unstructured":"NguyenKB BironCA . 1999. 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