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  • Review Article
  • Published:

Effector and regulatory B cells: modulators of CD4+ T cell immunity

Key Points

  • Clinical trial data have revealed that B cell depletion can be an effective therapy for a number of autoimmune diseases that are typically thought to be T cell dependent, such as type 1 diabetes, rheumatoid arthritis and multiple sclerosis. Despite the clinical efficacy of B cell depletion, autoantibody titres are often not affected, indicating that B cells can exacerbate autoimmune disease by both antibody-dependent and antibody-independent mechanisms.

  • In patients with pemphigus vulgaris or idiopathic thrombocytopenic purpura, rituximab-mediated B cell depletion leads to a decrease in the numbers of autoreactive CD4+ T cells and changes in T cell function. Similar results are observed following B cell depletion in mouse models of autoimmune disease, suggesting that B cells can amplify or sustain pathological autoimmune T cell responses.

  • Following CD20-specific antibody treatment of patients or mice with autoimmunity, regulatory T cells are expanded. This suggests that B cell depletion promotes the re-emergence of T cells that can suppress autoreactive immune responses.

  • The timing of B cell depletion therapy can dictate its effectiveness in autoimmune disease. In mouse models, early B cell depletion can accelerate and exacerbate autoimmune responses, but B cell depletion following the onset of disease can be therapeutic. These data suggest that B cells can be both protective and pathogenic and predict that B cells can be functionally subdivided into regulatory and effector subsets.

  • Data from mouse models of infectious and autoimmune disease show that B cells can enhance primary and memory CD4+ T cell responses, independently of antibody production. These results suggest that effector B cells can promote cellular immune responses by presenting antigen, providing co-stimulation and producing inflammatory and polarizing cytokines.

  • B cells might also function to downregulate immune responses through various mechanisms. B cells, at least in vitro, can enhance the development and proliferation of regulatory T cells, and IL-10-producing regulatory B cells can suppress effector T cell responses in vivo.

Abstract

B cells are essential for humoral immunity, but the role that they have in regulating CD4+ T cell responses remains controversial. However, new data showing that the transient depletion of B cells potently influences the induction, maintenance and reactivation of CD4+ T cells, with the recent identification of antibody-independent functions of B cells, have reinvigorated interest in the many roles of B cells in both infectious and autoimmune diseases. In this Review, we discuss recent data showing how effector and regulatory B cells modulate CD4+ T cell responses to pathogens and autoantigens.

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Figure 1: Resetting the effector and regulatory B and T cell networks after B cell depletion.
Figure 2: B cells both suppress and enhance T cell immunity.
Figure 3: Effector and regulatory B cells have opposing roles in immune responses.

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Acknowledgements

We gratefully acknowledge discussion and comments from W. Wojciechowski, R. Misra and B. Leon. This work was supported by US National Institutes of Health grants R01AI068056 and R01AI061511 and the University of Rochester.

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F.E.L. is a recipient of a research grant supported by Roche. The grant does not support research related to the topic of this Review. Roche is one of the manufacturers of the drug rituximab, which is discussed in this Review.

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Glossary

Transitional T2 B cells

Transitional B cells are short-lived immature B cells, typically found in the spleen, that either die or are selected into the peripheral mature B cell repertoire. Transitional B cells can be subdivided into three subsets (T1, T2 and T3 cells) based on differential phenotypic and functional characteristics.

Follicular B cell

A recirculating, mature B cell that populates the follicles of the spleen and lymph nodes.

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Lund, F., Randall, T. Effector and regulatory B cells: modulators of CD4+ T cell immunity. Nat Rev Immunol 10, 236–247 (2010). https://doi.org/10.1038/nri2729

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