Regulatory T cells and control of the germinal centre response.

Ine Vanderleyden,Kenneth Gc Smith,Michelle A Linterman

doi:10.1186/s13075-014-0471-7

Ine Vanderleyden, Kenneth Gc Smith + Show 1 more

Open Access

https://doi.org/10.1186/s13075-014-0471-7

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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.

Highlights

The establishment of antigen-specific memory responses is a key aspect of adaptive immunity that protects the host against future infections and forms the basis of successful immunisation
cytotoxic T-lymphocyte antigen 4 (CTLA-4) is expressed at high levels on regulatory T (Treg) cells and exerts its inhibitory function by depleting CD80/CD86 from the surface of antigen-presenting cells by trans-endocytosis, thereby inhibiting co-stimulatory signalling [47]. This inhibition results in failure of dendritic cell (DC) to activate T cells through CD28, thereby inhibiting priming of CD4+ T cells. These findings demonstrate that forkhead box p3 (Foxp3)+ Treg cells play a role in suppressing the initiation of the germinal centre (GC), and CTLA-4 is a probable effector mechanism by which Treg cells may mediate this suppression
follicular regulatory T (Tfr) cells are a subset of Foxp3+ Treg cells that adopt features of follicular helper T (Tfh) cells to enable them to migrate into the GC while maintaining their suppressive function

Summary

Introduction

The establishment of antigen-specific memory responses is a key aspect of adaptive immunity that protects the host against future infections and forms the basis of successful immunisation. In our study, mixed bone marrow chimaeras (SAP-deficient mice and Foxp3-DTR mice) were used to examine the effect of a specific reduction in Tfr cells on the GC response In this system, immunisation with a T-dependent antigen significantly increased the number of Tfh cells and GC B cells, indicating that Tfr cells can suppress features of the GC response in vivo. Because IL-10 deficiency in Foxp3+ Treg cells does not result in excessive autoantibody formation, it seems likely that IL-10 production by Tfr cells may play a minor role in controlling Tfh cells rather than mediating major suppressive effects. Tfr cells fit in a model in which Treg cells coopt aspects of specific Th cell differentiation pathways, enabling them to migrate to sites where these Th cells are functioning in immune responses Once there, their suppressive effects help ensure that collateral damage is minimised during the fight against infection

Conclusions

MacLennan IC