Facultative role for T cells in extrafollicular Toll-like receptor-dependent autoreactive B-cell responses in vivo

被引:53
|
作者
Sweet, Rebecca A. [1 ,2 ]
Ols, Michelle L. [2 ]
Cullen, Jaime L. [2 ]
Milam, Ashley Viehmann [1 ]
Yagita, Hideo [3 ]
Shlomchik, Mark J. [1 ,2 ]
机构
[1] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06520 USA
[2] Yale Univ, Sch Med, Dept Lab Med, New Haven, CT 06520 USA
[3] Juntendo Univ, Sch Med, Dept Immunol, Tokyo 113, Japan
关键词
systemic lupus; autoantibodies; SHORT-LIVED PLASMABLASTS; ANTIBODY-RESPONSES; SYSTEMIC AUTOIMMUNITY; SOMATIC HYPERMUTATION; GERMINAL-CENTERS; MURINE LUPUS; MOUSE MODEL; ACTIVATION; IL-21; MICE;
D O I
10.1073/pnas.1018571108
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Extrafollicular (EF) B-cell responses are increasingly being recognized as an alternative pathway of B-cell activation, particularly in autoimmunity. Critical cellular interactions required for the EF B-cell response are unclear. A key question in autoimmunity, in which Toll-like receptor (TLR) signals are costimulatory and could be sufficient for B-cell activation, is whether T cells are required for the response. This is pivotal, because autoreactive B cells are considered antigen-presenting cells for autoreactive T cells, but where such interactions occur has not been identified. Here, using AM14 site-directed transgenic rheumatoid factor (RF) mice, we report that B cells can be activated, differentiate, and isotype-switch independent of antigen-specific T-cell help, alpha beta T cells, CD40L signaling, and IL-21 signaling to B cells. However, T cells do dramatically enhance the response, and this occurs via CD40L and IL-21 signals. Surprisingly, the response is completely inducible T-cell costimulator ligand independent. These results establish that, although not required, T cells substantially amplify EF autoantibody production and thereby implicate T-independent autoreactive B cells as a potential vector for breaking T-cell tolerance. We suggest that these findings explain why autoreactivity first focuses on self-components for which B cells carry TLR ligands, because these will uniquely be able to activate B cells independently of T cells, with subsequent T-B interactions activating autoreactive T cells, resulting in chronic autoimmunity.
引用
收藏
页码:7932 / 7937
页数:6
相关论文
共 50 条
  • [1] Toll-like receptor mediated inflammation directs B cells towards protective antiviral extrafollicular responses
    Lam, Jonathan H.
    Baumgarth, Nicole
    NATURE COMMUNICATIONS, 2023, 14 (01)
  • [2] Regulation of B-cell responses by Toll-like receptors
    Browne, Edward P.
    IMMUNOLOGY, 2012, 136 (04) : 370 - 379
  • [3] Porcine B Cell Subset Responses to Toll-like Receptor Ligands
    Braun, Roman Othmar
    Python, Sylvie
    Summerfield, Artur
    FRONTIERS IN IMMUNOLOGY, 2017, 8
  • [4] Human and rhesus plasmacytoid dendritic cell and B-cell responses to Toll-like receptor stimulation
    Gujer, Cornelia
    Sundling, Christopher
    Seder, Robert A.
    Hedestam, Gunilla B. Karlsson
    Lore, Karin
    IMMUNOLOGY, 2011, 134 (03) : 257 - 269
  • [5] Systemic Toll-Like Receptor Ligands Modify B-cell Responses in Human Inflammatory Bowel Disease
    McDonnell, Marie
    Liang, YanMei
    Noronha, Ansu
    Coukos, Jennifer
    Kasper, Dennis L.
    Farraye, Francis A.
    Ganley-Leal, Lisa M.
    INFLAMMATORY BOWEL DISEASES, 2011, 17 (01) : 298 - 307
  • [6] A tolerogenic role for Toll-like receptor 9 is revealed by B-cell interaction with DNA complexes expressed on apoptotic cells
    Miles, Katherine
    Heaney, Jonathan
    Sibinska, Zaneta
    Salter, Donald
    Savill, John
    Gray, David
    Gray, Mohini
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2012, 109 (03) : 887 - 892
  • [7] Toll-like receptor ligands sensitize B-cell receptor signalling by reducing actin-dependent spatial confinement of the receptor
    Freeman, Spencer A.
    Jaumouille, Valentin
    Choi, Kate
    Hsu, Brian E.
    Wong, Harikesh S.
    Abraham, Libin
    Graves, Marcia L.
    Coombs, Daniel
    Roskelley, Calvin D.
    Das, Raibatak
    Grinstein, Sergio
    Gold, Michael R.
    NATURE COMMUNICATIONS, 2015, 6
  • [8] Toll-like receptors - sentries in the B-cell response
    Bekeredjian-Ding, Isabelle
    Jego, Gaetan
    IMMUNOLOGY, 2009, 128 (03) : 311 - 323
  • [9] Modulation of B cell responses by Toll-like receptors
    Booth, Jayaum
    Wilson, Heather
    Jimbo, Steve
    Mutwiri, George
    CELL AND TISSUE RESEARCH, 2011, 343 (01) : 131 - 140
  • [10] Endocytic sequestration of the B cell antigen receptor and toll-like receptor 9 in anergic cells
    O'Neill, Shannon K.
    Veselits, Margaret L.
    Zhang, Miao
    Labno, Christine
    Cao, Yanxia
    Finnegan, Alison
    Uccellini, Melissa
    Alegre, Maria-Luisa
    Cambier, John C.
    Clark, Marcus R.
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (15) : 6262 - 6267