B cells expressing the transcription factor T-bet drive lupus-like autoimmunity
Kira Rubtsova, Anatoly V. Rubtsov, Joshua M. Thurman, Johanna M. Mennona, John W. Kappler, Philippa Marrack
Kira Rubtsova, Anatoly V. Rubtsov, Joshua M. Thurman, Johanna M. Mennona, John W. Kappler, Philippa Marrack
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Research Article Autoimmunity Immunology

B cells expressing the transcription factor T-bet drive lupus-like autoimmunity

Abstract

B cells contribute to multiple aspects of autoimmune disorders and may play a role in triggering disease. Thus, targeting B cells may be a promising strategy for treating autoimmune disorders. Better understanding of the B cell subsets that are responsible for the development of autoimmunity will be critical for developing efficient therapies. Here we have reported that B cells expressing the transcription factor T-bet promote the rapid appearance of autoantibodies and germinal centers in spontaneous murine models of systemic lupus erythematosus (SLE). Conditional deletion of T-bet from B cells impaired the formation of germinal centers and mitigated the development of kidney damage and rapid mortality in SLE mice. B cell–specific deletion of T-bet was also associated with lower activation of both B cells and T cells. Taken together, our results suggest that targeting T-bet–expressing B cells may be a potential target for therapy for autoimmune diseases.

Authors

Kira Rubtsova, Anatoly V. Rubtsov, Joshua M. Thurman, Johanna M. Mennona, John W. Kappler, Philippa Marrack

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Figure 8

Model.

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Model. (A) Development of a lupus-like autoimmune response in the presen...
(A) Development of a lupus-like autoimmune response in the presence of B cell–intrinsic T-bet. Synergistic stimulation of B cells with autoantigen (auto-Ag), TLR ligand, and IFN-γ leads to the B cell–intrinsic T-bet expression (arrows a and b). T-bet+ B cells present auto-Ag to T cells (c), leading to subsequent T cell activation, IFN-γ production (d), and GC formation (h). Simultaneously, the GC reaction leads to further T cell activation (i) and differentiation of the B cells into autoantibody-producing (auto-Ab–producing) plasma cells (j). Finally, activated autoreactive T cells and autoantibody-producing plasma cells facilitate kidney damage (k and l). (B) The effect of B cell–intrinsic T-bet deletion on the development of the autoimmune response. Alternative pathway of B cell activation takes place when T-bet cannot be expressed by B cells (m), and also leads to the GC development and T cell activation (n and o); however, this pathway is delayed, less efficient, and generates less end-organ damage. Scale bars: 100 μm.