T follicular helper cells, T follicular regulatory cells and autoimmunity

Abstract

CD4(+)T follicular helper (Tfh) cells are recognized as a distinct T-cell subset, which provides help for germinal center (GC) formation, B-cell development and affinity maturation, and immunoglobulin class switching, as an indispensable part of adaptive immunity. Tfh cell differentiation depends on various factors including cell-surface molecule interactions, extracellular cytokines and multiple transcription factors, with B-cell lymphoma 6 (Bcl-6) being the master regulator. T follicular regulatory (Tfr) cells are also located in the GC and share phenotypic characteristics with Tfh cells and regulatory T cells, but function as negative regulators of GC responses. Dysregulation of either Tfh or Tfr cells is linked to the pathogenesis of autoimmune diseases such as systemic lupus erythematosus. This review covers the basic Tfh and Tfr biology including their differentiation and function, and their close relationship with autoimmune diseases.

Keywords: T follicular helper cell; T follicular regulatory cell; autoimmune diseases.

Fig. 1.

Interactions among Tfh, Tfr and B cells in GCs. Left, after priming by dendritic cells (DCs) in the T-cell zone, Tfh cells will up-regulate CXCR5 expression and then migrate to the T–B border to interact with cognate B cells. Interaction with B cells helps further commitment of Tfh cells and enhances CXCR5 expression. Similarly, thymus-derived T_reg cells migrate to the GC and differentiate to Tfr cells to interact with Tfh and B cells. Right, an enlarged view of cell–cell interactions in the follicle. GC Tfh cells provide help, via various mechanisms such as interaction between cell-surface molecules or production of cytokines like IL-21 for B-cell proliferation and somatic hypermutation, allowing them to differentiate into high-affinity plasma cells or memory B cells. In contrast, Tfr cells express the transcription factors Foxp3 and Bcl-6 and other molecules. Tfr cells constrain GC reactions via co-inhibitory receptors such as CTLA-4, secretion of inhibitory cytokines such as IL-10 and TGF-β, and cytotoxic effects by granzyme release. FDC, follicular dendritic cell.