Pathophysiology of T follicular helper cells in humans and mice

Abstract

Follicular helper T cells (TFH cells) compose a heterogeneous subset of CD4(+) T cells that induce the differentiation of B cells into plasma cells and memory cells. They are found within and in proximity to germinal centers in secondary lymphoid organs, and their memory compartment also circulates in the blood. Our knowledge on the biology of TFH cells has increased significantly during the past decade, largely as a result of mouse studies. However, recent studies on human TFH cells isolated from lymphoid organ and blood samples and recent observations on the developmental mechanism of human TFH cells have revealed both similarities and differences between human and mouse TFH cells. Here we present the similarities and differences between mouse and human lymphoid organ-resident TFH cells and discuss the role of TFH cells in response to vaccines and in disease pathogenesis.

Figure 1

Potential mechanism in the generation of human T_FH subsets. As with other T_H subsets, signals derived from antigen-presenting cells (including DCs) and the microenvironment instruct naive CD4⁺ T cells to differentiate into the T_FH lineage. The major cytokines driving the early T_FH differentiation process in humans are IL-12 and IL-23, and TGF-β synergizes with these cytokines. Other STAT3-activating cytokines, including IL-6, IL-21 and IL-1β, also support this process in the presence of IL-12, IL-23 and TGF-β. The differentiation of human naive CD4⁺ T cells is regulated by the balance of signals derived from these cytokines, and activated CD4⁺ T cells differentiate into precursors of variable T_H subsets such as T_H1, T_H17 and T_FH cells. Some T_FH precursors share properties of T_H1 and T_H17 cells (dotted rectangle in middle panel); interactions with B cells promote their differentiation into mature T_FH cells, including T_FH1 and T_FH17 cells. The mechanism associated with the generation of T_FH2 cells is currently unknown.

Figure 2

Alteration of blood memory T_FH subsets in human autoimmune diseases. (a) Three parameters—CXCR3 versus CCR6, PD-1 and CCR7, and ICOS—can subdivide human blood memory T_FH cells (CD4⁺CD45RA⁻CXCR5⁺) into at least three T_FH1, T_FH2 and T_FH17 subsets (nine T_FH subsets in total). PD-1 and CCR7 define two quiescent subpopulations, PD-1⁻CCR7^hi and PD-1⁺CCR7^int, and ICOS defines the ICOS⁺PD-1²⁺ activated population within the blood memory T_FH1, T_FH2 and T_FH17 subsets. The nine blood memory T_FH subsets are indicated in a three-dimensional scale. (b) T_FH2 and T_FH17 subsets represent efficient helpers among blood memory T_FH subsets. In the blood of patients with active autoimmune disease (such as SLE, juvenile dermatomyositis, Sjögren’s syndrome or multiple sclerosis), the frequency of active (ICOS⁺PD-1²⁺) T_FH2 and T_FH17 subsets increases, whereas the frequency of T_FH1 subsets decreases. This alteration likely reflects the increase of functional T_FH cells in lymphoid organs and/or inflamed tissues.

Figure 3

Risk loci of human autoimmune diseases associated with the T_FH developmental pathway. Multiple risk loci identified in GWAS in autoimmune diseases (indicated in red) are potentially associated with the regulation of the development and/or the function of human T_FH cells. At least seven risk loci—IL12A, IL12B, IL23R, STAT3, STAT4, IRF5 and IRF8—are associated with IL-12 and IL-23. IRF8 also might contribute to TGF-β signaling by promoting the expression of TGF-β-activating integrin α_vβ₈ on the surface of DCs. Risk loci contain genes encoding T_FH-specific molecules (such as IL21 and CXCR5), as well as genes associated with the inhibition of T_FH cell development (such as PRDM1 and PTPN22). Whether and how these gene variants are associated with aberrant T_FH responses in autoimmune diseases remains to be established.