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

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.

Figure 1. Resetting the effector and regulatory B and T cell networks after B cell depletion

The mechanistic basis for the effectiveness of B cell depletion in treating autoimmune disease is not understood. Based on the data, we propose a model in which autoreactive effector B and T cells establish a feed-forward loop that destroys the interconnected effector and regulatory B and T cell networks. B cell depletion allows for re-establishment of the regulatory network and favors development of tolerance upon B cell repopulation. In this model, a break in tolerance of either the B or T cell occurs (panel a), allowing for the initiation of cognate interactions between autoreactive T and B cells and the establishment of a B and T cell dependent feed-forward loop (panel b). This antigen-driven feed-forward loop eventually dominates the response and is no longer susceptible to suppression by regulatory B and T cells. When B cells are depleted (panel c), the T/B feed-forward loop is broken and the number of responding T cells decreases. This results in decreased inflammatory cytokine production by the autoreactive T and B cells favors the generation, expansion and function of regulatory T cells (panel d) that can suppress remaining autoreactive effector T cells. Finally, the transitional and naïve B cells that initially repopulate the patient (panel e) are likely to have regulatory or tolerance inducing capacity, similar to the B cells found in neonates. These B cells can drive the induction or expansion of new cohorts of regulatory T cells, resetting the balance of regulatory and effector T cells to favor tolerance rather than responsiveness.

Figure 2. B cells both suppress and enhance T cell mediated immunity

Depletion of B cells at different times following immunization can have drastically different consequences for T cells (ref 57), suggesting that B cells perform functionally and temporally distinct roles during immune responses. In unmanipulated animals, naïve and regulatory B and T cells are present but few effector cells are found. At early timepoints following immunization, antigen-specific effector T and B cells expand, however regulatory T and B cells are also expanding and can slow the proliferation of the effector T cells. Once the ratio of regulatory to effector cells is biased toward the effector response and the cytokine milieu is dominated by pro-inflammatory cytokines, then the regulatory loop is repressed and the B/T cell antigen-driven feedforward loop is established. When B cells are depleted early, before the immune response is initiated, the regulatory B and T cell loop is not established, leading to an unchecked effector T cell response. By contrast, when effector and regulatory B cells are depleted later in the immune response, then effector T cell expansion and inflammatory cytokine production are curtailed due to interruption of the effector T/B cell feed-forward loop. Regulatory B cells are also eliminated by the depletion therapy, but the remaining regulatory T cells which are no longer exposed to the high level inflammatory cytokines can expand and more efficiently suppress the remaining autoreactive effector T cells.

Figure 3. Effector and Regulatory B cells play opposing roles in immune responses

Effector and regulatory B cells can present antigen to CD4⁺ T cells and can provide co-stimulation and cytokines. Effector B cells (Be-1 and Be-2) can secrete cytokines such as IFNγ, IL-12, IL-4 and IL-2 that reinforce and stabilize the cytokine profile of effector T_H1 and T_H2 cells. In addition, the effector B cells can recruit additional naïve T cells into the inflammatory response. In contrast, the regulatory B cells produce IL-10 which suppresses the inflammatory potential of effector T cells, alters the activity of antigen-presenting DCs and promotes regulatory T cell development and expansion. Thus, effector B cells act as accelerators of CD4⁺ T cell responses while regulatory B cells act as brakes on the response. In autoimmune disease, the ratio between effector B and T cells and regulatory B and T cells likely favors the effector B cells. Drugs that selectively deplete the effector B cells may be highly effective in resetting this balance in favor of the regulatory populations.