A Public BCR Present in a Unique Dual-Receptor-Expressing Lymphocyte from Type 1 Diabetes Patients Encodes a Potent T Cell Autoantigen

被引：92

作者：

Ahmed, Rizwan ^{[1
]}

Omidian, Zahra ^{[1
]}

Giwa, Adebola ^{[2
]}

Cornwell, Benjamin ^{[1
]}

Majety, Neha ^{[1
]}

Bell, David R. ^{[3
]}

Lee, Sangyun ^{[3
]}

Zhang, Hao ^{[4
]}

Michels, Aaron ^{[5
]}

Desiderio, Stephen ^{[6
,7
]}

Sadegh-Nasseri, Scheherazade ^{[1
]}

Rabb, Hamid ^{[8
]}

Gritsch, Simon ^{[9
,10
,11
]}

Suva, Mario L. ^{[9
,10
,11
,12
]}

Cahan, Patrick ^{[6
,7
,8
]}

Zhou, Ruhong ^{[3
,13
]}

Jie, Chunfa ^{[14
]}

Donner, Thomas ^{[8
]}

Hamad, Abdel Rahim A. ^{[1
,8
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA

[3] IBM Thomas J Watson Res Ctr, Computat Biol Ctr, Yorktown Hts, NY 10598 USA

[4] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA

[5] Univ Colorado, Barbara Davis Ctr Diabet, Aurora, CO 80045 USA

[6] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA

[7] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Baltimore, MD 21205 USA

[8] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA

[9] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[10] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA

[11] Harvard Med Sch, Boston, MA 02114 USA

[12] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[13] Columbia Univ, Dept Chem, New York, NY 10027 USA

[14] Des Moines Univ, Dept Biochem & Nutr, Des Moines, IA 50312 USA

来源：

CELL | 2019年 / 177卷 / 06期

关键词：

B-CELLS; RNA-SEQ; DIVERSITY; RESPONSES; SEQUENCE; MICE; GENE; IG;

D O I：

10.1016/j.cell.2019.05.007

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

T and B cells are the two known lineages of adaptive immune cells. Here, we describe a previously unknown lymphocyte that is a dual expresser (DE) of TCR and BCR and key lineage markers of both B and T cells. In type 1 diabetes (T1D), DEs are predominated by one clonotype that encodes a potent CD4 T cell autoantigen in its antigen binding site. Molecular dynamics simulations revealed that this peptide has an optimal binding register for diabetogenic HLA-DQ8. In concordance, a synthetic version of the peptide forms stable DQ8 complexes and potently stimulates autoreactive CD4 T cells from T1D patients, but not healthy controls. Moreover, mAbs bearing this clonotype are autoreactive against CD4 T cells and inhibit insulin tetramer binding to CD4 T cells. Thus, compartmentalization of adaptive immune cells into T and B cells is not absolute, and violators of this paradigm are likely key drivers of autoimmune diseases.

引用

页码：1583 / +

页数：33

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