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Although the HLA class II locus is the strongest genetic risk factor for rheumatoid arthritis, the relationship between HLA class II alleles and lymphocyte activation remains unclear. We performed immunophenotyping of peripheral blood mononuclear cells on 91 HLA-DRB1-genotyped RA patients and 110 healthy donors. The frequency of memory CXCR4<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup>T cells and not Th1 and Th17 cells, was significantly associated with disease severity by multiple linear regression analysis. RA patients with one or more susceptible HLA-DR haplotypes (shared epitope: SE) displayed a significantly higher frequency of memory CXCR4<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup>T cells. Moreover, the frequency of memory CXCR4<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup>T cells significantly correlated with the expression level of HLA-DR on B cells, which was elevated in RA patients with SE.<jats:italic>In vitro<\/jats:italic>analysis and transcriptomic pathway analysis suggested that the interaction between HLA-DR and T cell receptors is an important regulator of memory CXCR4<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup>T cells. Clinically, a higher frequency of memory CXCR4<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup>T cells predicted a better response to CTLA4-Ig. Memory CXCR4<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup>T cells may serve as a powerful biomarker for unraveling the linkage between HLA-DRB1 genotype and disease activity in RA.<\/jats:p>","DOI":"10.1038\/srep29338","type":"journal-article","created":{"date-parts":[[2016,7,7]],"date-time":"2016-07-07T09:40:18Z","timestamp":1467884418000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["Immunophenotyping of rheumatoid arthritis reveals a linkage between HLA-DRB1 genotype, CXCR4 expression on memory CD4+ T cells and disease activity"],"prefix":"10.1038","volume":"6","author":[{"given":"Yasuo","family":"Nagafuchi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirofumi","family":"Shoda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuji","family":"Sumitomo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichiro","family":"Nakachi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rika","family":"Kato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumi","family":"Tsuchida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruka","family":"Tsuchiya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiichi","family":"Sakurai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norio","family":"Hanata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoko","family":"Tateishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroko","family":"Kanda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuyoshi","family":"Ishigaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukinori","family":"Okada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akari","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Kochi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keishi","family":"Fujio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiko","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,7,7]]},"reference":[{"key":"BFsrep29338_CR1","doi-asserted-by":"publisher","first-page":"2205","DOI":"10.7748\/phc2011.11.21.9.29.c8797","volume":"365","author":"IB McInnes","year":"2011","unstructured":"McInnes, I. B. & Schett, G. The pathogenesis of rheumatoid arthritis. N Engl J Med 365, 2205\u20132219, 10.7748\/phc2011.11.21.9.29.c8797 (2011).","journal-title":"N Engl J Med"},{"key":"BFsrep29338_CR2","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1038\/nature12873","volume":"506","author":"Y Okada","year":"2014","unstructured":"Okada, Y. et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506, 376\u2013381, 10.1038\/nature12873 (2014).","journal-title":"Nature"},{"key":"BFsrep29338_CR3","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.1002\/art.1780301102","volume":"30","author":"PK Gregersen","year":"1987","unstructured":"Gregersen, P. K., Silver, J. & Winchester, R. J. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. 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