Regulatory T cells and control of the germinal centre response

Abstract

Germinal centres (GCs) are specialised lymphoid microenvironments that form in secondary B-cell follicles upon exposure to T-dependent antigens. In the GC, clonal expansion, selection and differentiation of GC B cells result in the production of high-affinity plasma cells and memory B cells that provide protection against subsequent infection. The GC is carefully regulated to fulfil its critical role in defence against infection and to ensure that immunological tolerance is not broken in the process. The GC response can be controlled by a number of mechanisms, one of which is by forkhead box p3 expressing regulatory T (Treg) cells, a suppressive population of CD4+ T cells. A specialised subset of Treg cells - follicular regulatory T (Tfr) cells - form after immunisation and are able to access the GC, where they control the size and output of the response. Our knowledge of Treg cell control of the GC is expanding. In this review we will discuss recent advances in the field, with a particular emphasis on the differentiation and function of Tfr cells in the GC.

Figure 1

Extrafollicular Foxp3 ⁺ regulatory T cells control the initiation of the germinal centre response. (A) During the early germinal centre (GC) response, Foxp3⁺ regulatory T (Treg) cells promote the immune response by IL-2 consumption. (B) A model of Foxp3⁺ Treg cell-mediated GC suppression by cytotoxic T-lymphocyte antigen 4 (CTLA-4). CTLA-4 is able to trans-endocytose CD80/86 from the dendritic cell (DC), thereby inhibiting co-stimulatory signalling through CD28 on the CD4⁺ T cells. Defective T-cell priming will result in failure of follicular helper T (Tfh) cell differentiation. Foxp3, forkhead box p3; MHC-II, major histocompatibility complex class II; TCR, T-cell receptor.

Figure 2

Follicular helper T cells and follicular regulatory T cells have different kinetic profiles. C57BL/6 mice were immunised intraperitoneally with sheep red blood cells (SRBC) and the numbers of splenic follicular helper T (Tfh) cells and follicular regulatory T (Tfr) cells were assessed by flow cytometry at different time points. During the germinal centre response, Tfh cells peak slightly earlier compared with Tfr cells. Tfh cell numbers peak around days 7 to 11 whereas the highest number of Tfr cells can be observed from days 11 to 17.

Figure 3

Follicular regulatory T cells control the output of the germinal centre response. Direct suppression of germinal centre B cells might occur through cytotoxic T-lymphocyte antigen 4 (CTLA-4)-mediated inhibition of CD80/CD86 co-stimulatory signalling. Alternatively, follicular regulatory T (Tfr) cell-mediated suppression may take place in an indirect manner by means of IL-10 secretion acting on follicular helper T (Tfh) cells. DZ, dark zone; FDC, follicular dendritic cells; LZ, light zone.