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To understand how distinct \u03b3\u03b4 T cell subsets are generated, we have developed a Two\u2010Stage model for \u03b3\u03b4 T cell development. This model is predicated on the finding that \u03b3\u03b4TCR signal strength impacts E protein activity through graded upregulation of Id3. Our model proposes that cells enter Stage 1 in response to a \u03b3\u03b4TCR signaling event in the cortex that activates a \u03b3\u03b4 T cell\u2013specific gene network. Part of this program includes the upregulation of chemokine receptors that guide them to the medulla. In the medulla, Stage 1 cells receive distinct combinations of \u03b3\u03b4TCR, cytokine, and\/co\u2010stimulatory signals that induce their transit into Stage 2, either toward the \u03b3\u03b4T1 or the \u03b3\u03b4T17 lineage. The intersection between \u03b3\u03b4TCR and cytokine signals can tune Id3 expression, leading to different outcomes even in the presence of strong \u03b3\u03b4TCR signals. The thymic signaling niches required for \u03b3\u03b4T17 development are segregated in time and space, providing transient windows of opportunity during ontogeny. Understanding the regulatory context in which E proteins operate at different stages will be key in defining how their activity levels impose functional outcomes.<\/jats:p>","DOI":"10.1111\/imr.12924","type":"journal-article","created":{"date-parts":[[2020,10,15]],"date-time":"2020-10-15T14:54:52Z","timestamp":1602773692000},"page":"181-197","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Interaction between \u03b3\u03b4TCR signaling and the E protein\u2010Id axis in \u03b3\u03b4 T cell development"],"prefix":"10.1111","volume":"298","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8820-5910","authenticated-orcid":false,"given":"Michele K.","family":"Anderson","sequence":"first","affiliation":[{"name":"Biological Sciences Sunnybrook Research Institute  Toronto ON Canada"},{"name":"Department of Immunology University of Toronto  Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3713-6302","authenticated-orcid":false,"given":"Johanna S.","family":"Selvaratnam","sequence":"additional","affiliation":[{"name":"Biological Sciences Sunnybrook Research Institute  Toronto ON Canada"},{"name":"Department of Immunology University of Toronto  Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,10,15]]},"reference":[{"issue":"22","key":"e_1_2_17_2_1","doi-asserted-by":"crossref","first-page":"10917","DOI":"10.1073\/pnas.1818256116","article-title":"Clonal Vgamma6(+)Vdelta4(+) T cells promote IL\u201017-mediated immunity against Staphylococcus aureus skin infection","volume":"116","author":"Marchitto MC","year":"2019","journal-title":"Proc Natl Acad Sci U S 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