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Events downstream of OX40L\/OX40 interaction in Tregs responsible for this novel mechanism are not understood. Earlier, OX40L\/OX40 interaction has been shown to stimulate CD4<jats:sup>+<\/jats:sup>T-cells through the formation of a signalosome involving TRAF2\/PKC-\u0472 leading to NF-kB activation. In this study, using CD4<jats:sup>+<\/jats:sup>T-cells from WT and OX40<jats:sup>\u2212\/\u2212<\/jats:sup>mice we first established that OX40 mediated activation of NF-kB was critical for this Treg proliferation. Although CD4<jats:sup>+<\/jats:sup>T-cells from PKC-\u0472<jats:sup>\u2212\/\u2212<\/jats:sup>mice were also defective in G-BMDC induced Treg proliferation<jats:italic>ex vivo<\/jats:italic>, this defect could be readily corrected by adding exogenous IL-2 to the co-cultures. Furthermore, by treating WT, OX40<jats:sup>\u2212\/\u2212<\/jats:sup>, and PKC-\u0472<jats:sup>\u2212\/\u2212<\/jats:sup>mice with soluble OX40L we established that OX40L\/OX40 interaction was required and sufficient to induce Treg proliferation<jats:italic>in vivo<\/jats:italic>independent of PKC-\u0472 status. Although PKC-\u0472 is dispensable for TCR-independent Treg proliferation per se, it is essential for optimum IL-2 production by Teff cells. Finally, our findings suggest that OX40L binding to OX40 likely results in recruitment of TRAF1 for downstream signalling.<\/jats:p>","DOI":"10.1038\/s41598-017-05254-8","type":"journal-article","created":{"date-parts":[[2017,7,20]],"date-time":"2017-07-20T13:58:28Z","timestamp":1500559108000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["PKC-\u0473 is dispensable for OX40L-induced TCR-independent Treg proliferation but contributes by enabling IL-2 production from effector T-cells"],"prefix":"10.1038","volume":"7","author":[{"given":"Khaled","family":"Alharshawi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandra","family":"Marinelarena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prabhakaran","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osama","family":"El-Sayed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Palash","family":"Bhattacharya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuoming","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan L.","family":"Epstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay V.","family":"Maker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bellur S.","family":"Prabhakar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,7,26]]},"reference":[{"key":"5254_CR1","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1038\/383787a0","volume":"383","author":"AK Abbas","year":"1996","unstructured":"Abbas, A. 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