Mechanisms by Which B Cells and Regulatory T Cells Influence Development of Murine Organ-Specific Autoimmune Diseases

Abstract

Experiments with B cell-deficient (B-/-) mice indicate that a number of autoimmune diseases require B cells in addition to T cells for their development. Using B-/- Non-obese diabetic (NOD) and NOD.H-2h4 mice, we demonstrated that development of spontaneous autoimmune thyroiditis (SAT), Sjogren's syndrome and diabetes do not develop in B-/- mice, whereas all three diseases develop in B cell-positive wild-type (WT) mice. B cells are required early in life, since reconstitution of adult mice with B cells or autoantibodies did not restore their ability to develop disease. B cells function as important antigen presenting cells (APC) to initiate activation of autoreactive CD4+ effector T cells. If B cells are absent or greatly reduced in number, other APC will present the antigen, such that Treg are preferentially activated and effector T cells are not activated. In these situations, B-/- or B cell-depleted mice develop the autoimmune disease when T regulatory cells (Treg) are transiently depleted. This review focuses on how B cells influence Treg activation and function, and briefly considers factors that influence the effectiveness of B cell depletion for treatment of autoimmune diseases.

Keywords: APC; B cells; autoimmunity; effector T cells; regulatory T cells.

Figure 1

T regulatory cells (Treg) from B−/− mice are more effective at suppressing spontaneous autoimmune thyroiditis (SAT) than Treg from wild-type (WT) mice. T cells from CD28−/−B−/− Non-obese diabetic (NOD).H-2h4 mice were cultured with or without Treg from WT or B−/− NOD.H-2h4 mice. TCR−/− NOD.H-2h4 recipients were given 5 × 10⁶ cultured T cells, and were given NaI in their drinking water. The no transfer group did not receive T cells. Thyroids were removed 8 weeks later. ** p < 0.01; *** p < 0.001, n.s., not significant. Results are the mean SAT severity scores from individual recipient mice. See [63] for additional details.

Figure 2

Repopulating Treg have reduced suppressive function compared to endogenous Treg. Treg were depleted by injection of anti-CD25 (Foxp3-GFP.NOD.H-2h4 mice) or diphtheria toxin (DT) (Foxp3-DTR NOD.H-2h4 mice. Treg were allowed to repopulate the spleen, and repopulating or control (endogenous) Treg were cultured with naïve T cells from CD28−/−B−/− NOD.H-2h4 mice. Groups of TCR−/− NOD.H-2h4 recipient mice were given T cells cultured with or without Treg, and all mice were given NaI water for 8 weeks. (A): n = 11 mice/group; (B): n = 9 mice/group. ** p < 0.01; *** p < 0.001. Results are mean SAT severity scores from groups of 9–11 recipients ± SEM. Additional details are in [63].

Figure 3

Interactions between Treg, B cells and effector T cells (Teff) in development of autoimmune diseases. (A) When B cells are absent or reduced in number (e.g., after anti-CD20 treatment), B cells are not available to present autoantigen. Presentation of autoantigen by other antigen-presenting cells (APC) results in little expansion or activation of naïve T helper (Th) cells and they do become Teff. However, Treg may expand and they are activated, and autoimmune disease does not develop because Treg activity is dominant. When Treg are depleted, presentation of autoantigen by non B cells leads to activation and expansion of naïve Th, they become Teff and autoimmunity develops; (B) B cells are present and able to function as APC. Naïve Th expand and become activated. Presentation of antigen to Treg may also lead to their activation, but Th activation is dominant. Suppression by Treg is insufficient to prevent autoimmune disease. Over time, Treg can produce Interleukin (IL)-10 and IL-35 leading to expansion of B regulatory cells (Breg) which suppress activated Th and effector B cells. Expanded Th produce proinflammatory cytokines and interact with B cells to promote their activation and production of autoantibody. Proinflammatory cytokines produced by B cells can also interfere with Treg function and/or activation, rendering suppression by Treg less effective. The dominant outcome is autoimmune disease.

Figure 3

Interactions between Treg, B cells and effector T cells (Teff) in development of autoimmune diseases. (A) When B cells are absent or reduced in number (e.g., after anti-CD20 treatment), B cells are not available to present autoantigen. Presentation of autoantigen by other antigen-presenting cells (APC) results in little expansion or activation of naïve T helper (Th) cells and they do become Teff. However, Treg may expand and they are activated, and autoimmune disease does not develop because Treg activity is dominant. When Treg are depleted, presentation of autoantigen by non B cells leads to activation and expansion of naïve Th, they become Teff and autoimmunity develops; (B) B cells are present and able to function as APC. Naïve Th expand and become activated. Presentation of antigen to Treg may also lead to their activation, but Th activation is dominant. Suppression by Treg is insufficient to prevent autoimmune disease. Over time, Treg can produce Interleukin (IL)-10 and IL-35 leading to expansion of B regulatory cells (Breg) which suppress activated Th and effector B cells. Expanded Th produce proinflammatory cytokines and interact with B cells to promote their activation and production of autoantibody. Proinflammatory cytokines produced by B cells can also interfere with Treg function and/or activation, rendering suppression by Treg less effective. The dominant outcome is autoimmune disease.