Follicular helper T (Tfh) cells provide selection signals to germinal center B cells, which is essential for long-lived antibody responses. High CXCR5 and low CCR7 expression facilitates their homing to B cell follicles and distinguishes them from T helper 1 (Th1), Th2, and Th17 cells. Here, we showed that Bcl-6 directs Tfh cell differentiation: Bcl-6-deficient T cells failed to develop into Tfh cells and could not sustain germinal center responses, whereas forced expression of Bcl-6 in CD4(+) T cells promoted expression of the hallmark Tfh cell molecules CXCR5, CXCR4, and PD-1. Bcl-6 bound to the promoters of the Th1 and Th17 cell transcriptional regulators T-bet and RORgammat and repressed IFN-gamma and IL-17 production. Bcl-6 also repressed expression of many microRNAs (miRNAs) predicted to control the Tfh cell signature, including miR-17-92, which repressed CXCR5 expression. Thus, Bcl-6 positively directs Tfh cell differentiation, through combined repression of miRNAs and transcription factors.

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.

Bcl-6 expression in CD4+ T cells is required to generate extrafollicular antibody responses.

1. Evidence gathered in recent years has revealed microRNAs (miRNAs) fine-tune gene expression and play an important role in various cellular processes, including cell growth, differentiation, proliferation and apoptosis. 2. The present review summarizes current knowledge of miRNA pathways in the pathogenesis of cancer, cardiac diseases, neurodegenerative diseases, diabetes, autoimmune/inflammatory diseases and infection. 3. There is considerable potential to target miRNAs as a novel approach in the treatment of human diseases. Currently, miRNA-based therapies are being examined in both animal models and human clinical trials.

The generation of immunological memory during an immune response is a hallmark of the adaptive immune system. Follicular helper T (Tfh) cells are a CD4 þ T-cell subset specialised to regulate antibody response. Emerging evidence suggests that during antibody response, Tfh memory is generated along with the generation of B-cell memory. There are multiple layers for the differentiation and function of memory Tfh cells. Both early committed precursor Tfh cells and effector Tfh cells exiting germinal centres can contribute to the memory Tfh pool. Functionally, memory Tfh cells not only enhance a secondary response upon antigen rechallenge but also circulate to non-draining lymph tissues to differentiate into effector Tfh cells in the face of systemic antigen/pathogen spreading, thus also promoting a primary response. Circulating memory Tfh cells are a valuable marker to monitor the Tfh programme in human autoimmune diseases, infections and vaccinations. Future studies are required to understand the molecular mechanisms determining the commitment and plasticity of Tfh memory and hence the physiological functions of Tfh memory. Keywords: Tfh; memory; antibody; plasticity Host detection of invading pathogens triggers a cascade of events that culminate in the recruitment and differentiation of leukocytes, including lymphocytes, suited to eliminate the pathogen. The generation of memory from efficacious immune response provides long-term protection against the pathogen. For humoral immune memory, long-lived plasma cells sustain antibody levels, whereas memory B cells respond rapidly upon antigen rechallenge. 1 As a result, omnipresent high-affinity serum antibodies prevent pathogens from entering or damaging host cells, mediate opsonisation, increase the efficiency of antigen presentation through the formation of immune complexes and stimulate immune responses via Fc (Fragment, crystallisable) or complement receptors.Cognate helper from CD4 þ helper T cells is essential at each step to generate B-cell memory: B-cell priming, germinal centre (GC) formation, selection and development of long-lived plasma cells and memory B cells, and memory B-cell response upon antigen rechallenge. 2 Although the generation and function of B-cell memory have been studied extensively (see ), the generation and function of cognate helper T-cell memory has not enjoyed as much limelight. Follicular B helper T (Tfh) cells are a CD4 þ helper T-cell subset specialised to provide cognate help to B cells. [3][4][5][6][7] In this review, we will focus on recent evidence for the formation of Tfh memory. As many important questions remain unanswered, the discussion here hopefully will inspire further investigation. THE NEED FOR TFH MEMORY-LEARNING FROM B-CELL MEMORYIn a recall antibody response, memory B cells undergo accelerated clonal expansion and rapid differentiation to high-affinity plasma cells or GC B cells. There are contradictory results on whether cognate T-cell help is required for memory B cells to respond in a recall response. CD4 þ hel...