Pursuing a germinal centre career

Antigen-primed B cells form germinal centres, where, helped by follicular helper T (T_FH) cells, they develop into high-affinity plasma and memory B cells. This process is under stringent control to avoid uncontrolled B cell proliferation and production of autoantibodies. Now, two studies published in Nature Medicine report that germinal centre reactions are controlled by regulatory T (T_Reg) cells with a T_FH cell-like phenotype.

The two studies identified forkhead box P3 (FOXP3)⁺ T_Reg cells expressing the T_FH cell-associated factors CXC-chemokine receptor 5 (CXCR5) and B cell lymphoma 6 (BCL-6) in the germinal centres of immunized mice. These follicular T_Reg cells expressed both T_FH cell-associated and T_Reg cell-associated genes and were suppressive in vitro.

So, do follicular T_Reg cells develop from T_FH or T_Reg cells? Adoptive transfer experiments indicated that follicular T_Reg cells originate from T_Reg cells. Moreover, Linterman et al. showed that thymus-derived but not induced T_Reg cells are the follicular T_Reg cell progenitors. In addition, they observed that, similarly to T_FH cells, follicular T_Reg cells require signalling through CD28 and SLAM-associated protein (SAP) for their generation, and both studies demonstrated that BCL-6 expression is essential for their differentiation. Thus, BCL-6 expression and SAP-mediated signalling lead to the development of follicular T_Reg cells from natural T_Reg cells.

But what is the function of follicular T_Reg cells? To address this, Linterman et al. generated chimeric mice that contained SAP-deficient T cells (which cannot differentiate into T_FH or follicular T_Reg cells), as well as T cells expressing the diphtheria toxin receptor under the control of the Foxp3 promoter. Selective depletion of follicular T_Reg cells with diphtheria toxin resulted in increased numbers of T_FH cells and germinal centre B cells in response to immunization. Intriguingly, the numbers of non-antigen-specific B cells were increased, whereas the percentages of antigen-specific plasma cells and memory B cells were reduced in chimeric mice lacking follicular T_Reg cells, compared with the numbers in control chimaeras. Thus, the authors suggest that follicular T_Reg cells limit T_FH cell numbers, and possibly select against those that are self-reactive, thereby providing a competitive advantage to high-affinity antigen-specific B cells.

By contrast, Chung et al. observed no increase in T_FH cell numbers in response to immunization when they transferred naive CD4⁺ T cells together with BCL-6- or CXCR5-deficient T_Reg cells (which cannot differentiate into follicular T_Reg cells) into T cell-deficient recipients. In their model, the absence of follicular T_Reg cells resulted in increased numbers of germinal centre B cells but also in elevated levels of antigen-specific B cells and high-affinity immunoglobulins.

Taken together, the two studies describe the BCL-6-dependent differentiation of natural T_Reg cells into follicular T_Reg cells, which negatively regulate germinal centre B cell numbers. The seemingly opposing conclusions on the effect of follicular T_Reg cells on antigen-specific B cell responses may rely on the experimental approaches used, and further research will clarify the contribution of follicular T_Reg cells to the regulation of germinal centre reactions.