The link between circulating follicular helper T cells and autoimmunity

Abstract

Follicular helper T (T_FH) cells provide help to B cells, supporting the formation of germinal centres that allow affinity maturation of antibody responses. Although usually located in secondary lymphoid organs, T cells bearing features of T_FH cells can also be identified in human blood, and their frequency and phenotype are often altered in people with autoimmune diseases. In this Perspective article, I discuss the increase in circulating T_FH cells seen in autoimmune settings and explore potential explanations for this phenomenon. I consider the multistep regulation of T_FH cell differentiation by the CTLA4 and IL-2 pathways as well as by regulatory T cells and highlight that these same pathways are crucial for regulating autoimmune diseases. The propensity of infection to serve as a cue for T_FH cell differentiation and a potential trigger for autoimmune disease development is also discussed. Overall, I postulate that alterations in pathways that regulate autoimmunity are coupled to alterations in T_FH cell homeostasis, suggesting that this population may serve as a core sentinel of dysregulated immunity.

Fig. 1. Blood-borne cT_FH cells are clonally related to their lymphoid counterparts.

Follicular helper T (T_FH) cells classically reside in secondary lymphoid organs where they support germinal centre (GC) B cell responses; however, T cells with similar markers can be detected in the lymph and blood. These circulating T_FH (cT_FH) cells have a memory phenotype and do not depend on GCs as they can arise in the context of SLAM-associated protein (SAP) deficiency, which abrogates sustained T cell–B cell interactions. However, they do require B cells, as cT_FH cell frequencies are greatly reduced in individuals with B cell deficiency. Blocking lymph node exit, by treatment with FTY720, dramatically decreases cT_FH cells in mice and humans^,,. Clonotype sharing reveals a developmental relationship between T_FH cells found in the GC and the blood^, and those found in the lymph and the blood, suggesting that T cell–B cell interactions at the T cell–B cell border give rise to both GC T_FH cells and cT_FH cells. It is possible that some GC T_FH cells enter the circulation from GCs but this is likely to be rare. Follicular regulatory T (T_FR) cells also have circulating counterparts (cT_FR); however, these have an immature phenotype and differentiate from regulatory T cells without the requirement for contact with B cells.

Fig. 2. IL-2-based inhibition of T_FH cells and adaptations to subvert this.

a | IL-2 plays an important role in promoting FOXP3⁺ regulatory T (T_reg) cell homeostasis; T_reg cell-deficient mice and humans exhibit increased follicular helper T (T_FH) cell numbers. b | During T cell priming, IL-2-induced signalling through the IL-2 receptor (IL-2R) upregulates BLIMP1 expression, skewing the BLIMP1 to BCL-6 ratio and inhibiting T_FH cell differentiation^–. Transforming growth factor-β (TGFβ) decreases IL-2R signalling by suppressing CD25 (IL-2Rα) expression. c | CD25-expressing dendritic cells (DCs) in the outer T cell zone can capture local IL-2, favouring T_FH cell differentiation. d | Within the germinal centre (GC), IL-6 can desensitize IL-2R signalling in mature T_FH cells by downregulating the IL-2R subunit CD122 (IL-2Rβ). APC, antigen-presenting cell; CTLA4, cytotoxic T lymphocyte antigen 4; CXCR5, CXC-chemokine receptor 5; FDC, follicular dendritic cell; ICOS, inducible T cell costimulator; ICOSL, ICOS ligand; PD1, programmed cell death protein 1; TCR, T cell receptor.

Fig. 3. Common pathways control autoimmune susceptibility and T_FH cell homeostasis.

In healthy individuals, follicular helper T (T_FH) cell homeostasis is maintained by the CTLA4 pathway and regulatory T (T_reg) cells as well as by IL-2. Defects in the IL-2–IL-2R pathway can increase T_FH cell numbers, and single nucleotide polymorphisms (SNPs) in the IL-2 pathway are associated with autoimmune disease. Altered CTLA4 expression or trafficking (for example, owing to LRBA mutations) or defects in T_reg cells can increase T_FH cell numbers and are also associated with autoimmune disease susceptibility. CTLA4, cytotoxic T lymphocyte antigen 4; CXCR5, CXC-chemokine receptor 5; ICOS, inducible T cell costimulatory; PD1, programmed cell death protein 1; TCR, T cell receptor.