{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:41:40Z","timestamp":1790775700614,"version":"4.1.0"},"reference-count":168,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2020,12,7]],"date-time":"2020-12-07T00:00:00Z","timestamp":1607299200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunological Reviews"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Once alerted to the presence of a pathogen, activated CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells initiate distinct gene expression programs that produce multiple functionally specialized T helper (Th) subsets. The cytokine milieu present at the time of antigen encounter instructs CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells to differentiate into interferon\u2010(IFN)\u2010\u03b3\u2010producing Th1 cells, interleukin\u2010(IL)\u20104\u2010producing Th2 cells, IL\u201017\u2010producing Th17 cells, follicular T helper (Tfh) cells, or regulatory T (Treg) cells. In each of these Th cell subsets, a single transcription factor has been identified as a critical regulator of its specialized differentiation program. In this context, the expression of the \u201cmaster regulator\u201d is necessary and sufficient to activate lineage\u2010specific genes while restricting the gene expression program of alternative Th fates. Thus, the transcription factor T\u2010bet controls Th1 differentiation program, while the development of Th2, Th17, Tfh, and Treg cells is dependent on transcription factors GATA3, ROR\u03b3t, Bcl6, and Foxp3, respectively. Nevertheless, master regulators or, more precisely, lineage\u2010defining transcription factors do not function in isolation. In fact, they interact with a complex network of transcription factors, orchestrating cell lineage specification programs. In this review, we discuss the concept of the combinatorial interactions of key transcription factors in determining helper T cell identity. Additionally, lineage\u2010defining transcription factors have well\u2010established functions beyond their role in CD4\n                    <jats:sup>+<\/jats:sup>\n                    Th subsets. They play critically important functions at distinct stages during T cell development in the thymus and they control the development of innate lymphoid cells (ILCs) in the bone marrow. In tracking the journey of T cells traversing from the thymus to the periphery and during the immune response, we discuss in broad terms developmental stage and context\u2010dependent functions of lineage\u2010defining transcription factors in regulating specification programs of innate and adaptive lymphocytes.\n                  <\/jats:p>","DOI":"10.1111\/imr.12935","type":"journal-article","created":{"date-parts":[[2020,12,8]],"date-time":"2020-12-08T01:33:23Z","timestamp":1607391203000},"page":"65-81","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Transcriptional regulation of adaptive and innate lymphoid lineage specification"],"prefix":"10.1111","volume":"300","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3439-7283","authenticated-orcid":false,"given":"Camille A.","family":"Spinner","sequence":"first","affiliation":[{"name":"Experimental Immunology Branch National Cancer Institute National Institutes of Health Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5783-7130","authenticated-orcid":false,"given":"Vanja","family":"Lazarevic","sequence":"additional","affiliation":[{"name":"Experimental Immunology Branch National Cancer Institute National Institutes of Health Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,12,7]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.ai.2015.09.002"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-00426-6"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1302259"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2292"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/86302"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.07.035"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1175870"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1176676"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80702-3"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.07.002"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80240-8"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2014.05.038"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2008.11.005"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI37865"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1415675112"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1993"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.12.004"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.1RI0418-152RR"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1003852107"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.01.002"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20101376"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.07.001"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2005.01.016"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05543"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni904"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature22360"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1731"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1172702"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07674"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.5.2730"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.03.030"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-08-3103"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(04)00076-7"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2007.07.010"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.10.010"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2294"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.06.018"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.06.017"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.11.008"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-06-440065"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(03)00328-5"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.10.6650"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI57456"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.01.012"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.288.5475.2369"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni1022"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0806472105"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa9420"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1684"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2014.03.001"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.08.007"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.09.016"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1228309"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12037"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.09.044"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","D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