Follicular B helper T (Tfh) cells support high affinity and long-term antibody responses. Here we found that within circulating CXCR5⁺ CD4⁺ T cells in humans and mice, the CCR7(lo)PD-1(hi) subset has a partial Tfh effector phenotype, whereas CCR7(hi)PD-1(lo) cells have a resting phenotype. The circulating CCR7(lo)PD-1(hi) subset was indicative of active Tfh differentiation in lymphoid organs and correlated with clinical indices in autoimmune diseases. Thus the CCR7(lo)PD-1(hi) subset provides a biomarker to monitor protective antibody responses during infection or vaccination and pathogenic antibody responses in autoimmune diseases. Differentiation of both CCR7(hi)PD-1(lo) and CCR7(lo)PD-1(hi) subsets required ICOS and BCL6, but not SAP, suggesting that circulating CXCR5⁺ helper T cells are primarily generated before germinal centers. Upon antigen reencounter, CCR7(lo)PD-1(hi) CXCR5⁺ precursors rapidly differentiate into mature Tfh cells to promote antibody responses. Therefore, circulating CCR7(lo)PD-1(hi) CXCR5⁺ CD4⁺ T cells are generated during active Tfh differentiation and represent a new mechanism of immunological early memory.

Systemic lupus erythematosus (SLE) is a potentially life-threatening autoimmune disease characterized by altered balance of activity between effector and regulatory CD4(+) T cells. The homeostasis of CD4(+) T cell subsets is regulated by interleukin (IL)-2, and reduced production of IL-2 by T cells is observed in individuals with SLE. Here we report that treatment with low-dose recombinant human IL-2 selectively modulated the abundance of regulatory T (Treg) cells, follicular helper T (TFH) cells and IL-17-producing helper T (TH17) cells, but not TH1 or TH2 cells, accompanied by marked reductions of disease activity in patients with SLE.

Overactivity of the germinal center (GC) pathway resulting from accumulation of follicular helper T (Tfh) cells causes autoimmunity, underscoring the need to understand the factors that control Tfh cell homeostasis. Here we have identifed posttranscriptional repression of interferon-γ (Ifng) mRNA as a mechanism to limit Tfh cell formation. By using the sanroque lupus model, we have shown that decreased Ifng mRNA decay caused excessive IFN-γ 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-γ receptor (IFN-γR) deficiency prevented lupus development. IFN-γ blockade reduced Tfh cells and autoantibodies, demonstrating that IFN-γ overproduction was required to sustain lupus-associated pathology. Increased IFN-γR signaling caused Bcl-6 overexpression in Tfh cells and their precursors. This link between IFN-γ and aberrant Tfh cell formation provides a rationale for IFN-γ blockade in lupus patients with an overactive Tfh cell-associated pathway.