Understanding pathogenic and physiological T follicular helper cell formation

Abstract

T follicular helper (Tfh) cells localize to follicles where they provide growth and selection signals to mutated germinal center (GC) B cells, thus promoting their differentiation into high affinity long-lived plasma cells and memory B cells. T-dependent B cell differentiation also occurs extrafollicularly, giving rise to unmutated plasma cells that are important for early protection against microbial infections. Bcl-6 expression in T cells has been shown to be essential for the formation of Tfh cells and GC B cells, but little is known about its requirement in physiological extrafollicular antibody responses. We use several mouse models in which extrafollicular plasma cells can be unequivocally distinguished from those of GC origin, combined with antigen-specific T and B cells, to show that the absence of T cell-expressed Bcl-6 significantly reduces T-dependent extrafollicular antibody responses. Bcl-6+ T cells appear at the T-B border soon after T cell priming and before GC formation, and these cells express low amounts of PD-1. Their appearance precedes that of Bcl-6+PD-1hi T cells, which are found within GC. IL-21 acts early to promote both follicular and extrafollicular antibody responses. In conclusion, Bcl6+ T cells are necessary at B cell priming in order to form extrafollicular antibody responses, and these pre-GC Tfh cells can be distinguished phenotypically from GC Tfh cells. Overactivity of the GC pathway due to accumulation of Tfh cells causes autoimmunity, underscoring the need to understand the factors that control Tfh homeostasis. Here, we have identified posttranscriptional repression of interferon-gamma (Ifng) mRNA as a novel mechanism to limit Tfh cell formation. Using the sanroque lupus model, we have shown that decreased Ifng mRNA decay caused excessive interferon-gamma signaling in T cells and led to accumulation of Tfh cells, spontaneous GC, autoantibody formation and nephritis. Unlike ICOS and T-bet deficiency that failed to rescue several autoimmune manifestations, interferon-gamma receptor deficiency completely prevented lupus development. Interferon-gamma blockade after disease onset reduced Tfh cells and autoantibodies, demonstrating that interferon-gamma overproduction was required to sustain lupus-associated pathology. Increased interferon-gamma signaling caused Bcl-6 overexpression in Tfh cells and their precursors. This novel link between interferon-gamma and aberrant Tfh formation provides a rationale for interferon-gamma blockade in lupus patients with an overactive Tfh cell-associated pathway.