Follicular Helper T Cells in Systemic Lupus Erythematosus

Abstract

CD4⁺ follicular helper T (Tfh) cells constitute a subset of effector T cells that participate in the generation of high-affinity humoral responses. They express the chemokine receptor CXCR5 and produce the cytokine IL-21, both of which are required for their contribution to germinal center formation. Uncontrolled expansion of Tfh cells is observed in various mouse models of systemic autoimmune diseases and in patients with these diseases. In particular, the frequency of circulating Tfh is correlated with disease activity and anti-DNA antibody titer in patients with systemic lupus erythematosus. Recent studies reveal functional diversity within the Tfh population in both humans and mice. We will summarize here the molecular mechanisms for Tfh cell generation, survival and function in both humans and mice, and the relationship between Tfh cells and autoimmune disease in animal models and in patients.

Keywords: autoimmunity; follicular helper T cells; human immunology; lupus models; transcription factors.

Figure 1

Subsets of circulating memory follicular helper T (Tfh) cells and their B cell activation. (A) The circulating CXCR5⁺ memory Tfh subsets. The minor CXCR5⁺ CD4⁺ T cells (1–5% of CXCR5⁺CD4⁺CD4⁺ T cells) express high levels of inducible co-stimulator (ICOS) and programmed cell death protein 1 (PD-1) and consist of CXCR3-positive or CXCR3-negative populations. The majority of CXCR5⁺ CD4⁺ T cells are low to negative in expression of ICOS and PD-1. These cells are subgrouped into Tfh1, Tfh2, and Tfh17 based on their chemokine receptor expression. These five subsets of Tfh cells express B cell lymphoma 6 as a master transcriptional regulator, and also express subset-specific transcription factors, effector cytokines, and activate naïve B cells to antibody-secreting cells. (B) CXCR5⁻ CD4⁺ T cells [peripheral helper T (Tph)] which express high level of PD-1 exhibit strong B cell activation. These Tph cells developed under inflamed conditions and are found in both inflamed tissue and blood. Solid color indicates high level of expression and patterned color indicates low level of expression.