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We investigated the cell landscape from three IgG4-RD retroperitoneal tissues and three control tissues using single-cell RNA-sequencing. Critical cell type or markers were further validated in the peripheral blood from the patients with IgG4-RD and healthy controls via flow cytometry as well as in the IgG4-RD and control tissue via immunofluorescence staining. The increases in B cells, plasma cells, and CD4+ T cells were found in IgG4-RD retroperitoneal tissue. Importantly, among CD4+ T cells, an increase in CD4+CXCR5\u2212PD1hi peripheral T helper (Tph) cells with a high expression of IL-21 and TIGIT was discovered in IgG4-RD tissue, which was further validated in peripheral blood of the patients with IgG4-RD. The Tph cell and TIGIT+ Tph cell proportion were remarkably higher in active IgG4-RD patients and correlated with disease activity. Moreover, TIGIT+CD4+ cells were able to promote B cell differentiation via IL-21. Our study revealed that Tph cells are increased in IgG4-RD and probably play critical roles in B cell differentiation through TIGIT-IL-21 axis. Peripheral Tph cell and TIGIT+Tph cell are potential markers for IgG4-RD disease activity.<\/jats:p>","DOI":"10.3390\/ijms241813735","type":"journal-article","created":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T10:07:37Z","timestamp":1693994857000},"page":"13735","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Single-Cell RNA-Sequencing Reveals Peripheral T Helper Cells Promoting the Development of IgG4-Related Disease by Enhancing B Cell Activation and Differentiation"],"prefix":"10.3390","volume":"24","author":[{"given":"Zongfei","family":"Ji","sequence":"first","affiliation":[{"name":"Department of Rheumatology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiqi","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sifan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China"},{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojuan","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiyong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China"},{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindi","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China"},{"name":"Evidence-Based Medicine Center, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiufang","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China"},{"name":"Evidence-Based Medicine Center, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/j.autrev.2010.05.003","article-title":"The birthday of a new syndrome: IgG4-related diseases constitute a clinical entity","volume":"9","author":"Takahashi","year":"2010","journal-title":"Autoimmun. 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