{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T03:10:39Z","timestamp":1791774639280,"version":"4.3.4"},"reference-count":56,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2009,11,10]],"date-time":"2009-11-10T00:00:00Z","timestamp":1257811200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Eur J Immunol"],"published-print":{"date-parts":[[2010,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Effector T\u2010cell responses can be modulated by competing positive or negative signals transduced by NK\u2010cell receptors (NKR). In the CD4<jats:sup>+<\/jats:sup> T\u2010cell population, the expression of NKR is primarily found in the CD4<jats:sup>+<\/jats:sup>CD28<jats:sup>\u2212<\/jats:sup> T\u2010cell subset, also known as CD28<jats:sup>null<\/jats:sup> T cells. These T cells are frequently found in rheumatoid arthritis (RA) and other inflammatory disorders, suggesting that signaling through NKR may play a role in the autoimmune reaction. Here we aimed to dissect the phenotype and function of NKR\u2010expressing CD4<jats:sup>+<\/jats:sup>CD28<jats:sup>\u2212<\/jats:sup> T cells in patients with RA. By analyzing a broad array of NKR on CD4<jats:sup>+<\/jats:sup>CD28<jats:sup>\u2212<\/jats:sup> T cells we found a significant expression of the co\u2010activating receptors 2B4 (CD244), DNAM\u20101 (CD226), and CRACC. Pair\u2010wise ligations of 2B4 with DNAM\u20101 and\/or NKG2D lead to increased effector functions of primary CD4<jats:sup>+<\/jats:sup>CD28<jats:sup>\u2212<\/jats:sup> T cells to suboptimal levels of anti\u2010CD3 stimulation. Using multi\u2010parameter flow cytometry, we demonstrate that such co\u2010ligation led to an increased magnitude in overall responsiveness without changing qualitative aspects of the response. Altogether these results demonstrate a pattern of additive effects in NKR\u2010mediated functional modulation of CD4<jats:sup>+<\/jats:sup>CD28<jats:sup>\u2212<\/jats:sup> T cells in RA. This may have consequences for the inflammatory responses imposed by these cells, thus influencing disease manifestations.<\/jats:p>","DOI":"10.1002\/eji.200939399","type":"journal-article","created":{"date-parts":[[2009,11,10]],"date-time":"2009-11-10T13:37:16Z","timestamp":1257860236000},"page":"378-387","source":"Crossref","is-referenced-by-count":70,"title":["Activating NK\u2010cell receptors co\u2010stimulate CD4<sup>+<\/sup>CD28<sup>\u2212<\/sup> T cells in patients with rheumatoid arthritis"],"prefix":"10.1002","volume":"40","author":[{"given":"Andreas E. 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