Talk 4: Follicular regulatory T cells in rheumatic diseases
Professor Luis Graca, Instituto de Medicina Molecular, Faculdade de Medicin, Universidade de Lisboa, Portugal
Germinal centres (GC) are anatomic structures where B cells undergo affinity maturation leading to production of high-affinity antibodies. The balance between T follicular helper (Tfh) and regulatory (Tfr) cells is critical for adequate control of GC responses. The study of human Tfh and Tfr cells’ development has been hampered due to the lack of in vitro assays reproducing the in vivo biology, along with difficult access to healthy human lymphoid tissues. We investigated the maturation of human Tfh and Tfr cells isolated from different human tissues using single cell transcriptomics, as well as samples from patients with rheumatic diseases. This way, it became possible to reconstruct the normal maturation trajectory for human Tfh and Tfr cells, and to uncover differences in their differentiation that are associated with autoimmune rheumatic diseases.
Talk 5: Ageing and the response to vaccination
Dr Michelle Linterman, Babraham Institute Cambridge, UK
Ageing dramatically affects the function of the immune system, resulting in increased susceptibility to infections and increased infection-related morbidity and mortality in older members of our communities. Notably, there is already an established intervention that can prevent a range of potentially life-threatening infections - vaccination. It has been observed, however, that older individuals often do not generate protective immunity after vaccination. The reasons for this are poorly understood, but it is clear that this leads to an increased prevalence of preventable disease in older people, even when good immunisation programmes are in place. At the heart of the immune response to vaccination is the germinal centre (GC) – a dynamic structure that forms in secondary lymphoid tissues after immunisation, and produces long-lived plasma cells, which secrete antibodies that block pathogens from establishing an infection, and memory B cells. A defining property of the GC is the collaboration of multiple cell types: proliferating B cells, T follicular helper cells (Tfh), T follicular regulatory cells (Tfr) and follicular dendritic cells to produce effector B cells of higher quality. With age, the magnitude of the GC response decreases resulting in impaired production of plasma cells, lower serum antibody levels and consequently, decreased protection against subsequent infection. Our research aims to understand how ageing affects the multiple cell types that participate in the GC response, and how we could mitigate the age-dependent changes with the goal of enhancing vaccine efficacy in older persons.
Additional Q&A for talks 4&5 and discussion
Talk 6: Regulation of CD11c+ T-bet+ B cells in autoimmunity
Professor Alessandra Pernis, Hospital for Special Surgery, Weill Cornell Medicine, USA
Studies in aging mice have recently identified a B cell subset, termed ABCs (Age/Autoimmune-associated B cells), which exhibits a unique phenotype and preferentially expands in females with age. In addition to classical B cell markers, ABCs also express T-bet and myeloid markers like CD11c hence these cells are also known as CD11c+ T-bet+ B cells. Formation of ABCs is promoted by a combination of signals that include TLR7 engagement and cytokines like IFN- and IL-21. Both murine and human studies have shown a close association between aberrant accumulation of ABCs and the development of autoimmunity. In particular, ABCs expand prematurely in murine lupus and produce pathogenic autoantibodies. Furthermore, expansion of human ABC-like cells (also known as Double Negative=DN or DN2 B cells) has been observed in SLE patients where they have been shown to be major producers of autoAbs and to correlate with disease activity and clinical manifestations. Here I will discuss work from our lab on the molecular pathways that regulate the expansion, function, and differentiation of ABCs in autoimmune settings.
Talk 7: Maintenance of Tfh cell identity and its impact on GCs
Professor Dirk Baumjohann, University Hospital Bonn, Germany
T follicular helper (Tfh) cells are crucial for the establishment of germinal centers (GCs) and potent antibody responses that are elicited during infection and vaccination. Despite their importance for humoral immunity, the T cell-intrinsic factors that are required for the maintenance of already established Tfh cells and GCs remain largely unknown.Temporally guided, tamoxifen-inducible CD4+ T cell-specific gene ablation was used to dissect the contributions of CXCR5, Bcl6, and mature miRNAs to the maintenance of Tfh cell function and identity. Induced ablation of Cxcr5 in CD4+ T cells had only minor effects on the identity and function of established Tfh cells. Phenotypical and transcriptional analyses revealed that Cxcr5-ablated cells still exhibited most features of CXCR5-positive Tfh cells. In contrast, continued Bcl6 expression was essential to maintain the GC Tfh cell phenotype and GC reaction. CD4+ T cell-specific Bcl6 ablation during acute viral infection resulted in transdifferentiation of established Tfh cells into Th1 cells. Finally, induced depletion of all mature miRNAs resulted in the loss of the Tfh cell phenotype and resolution of GCs. By highlighting the high degree of Tfh cell plasticity, these studies provide novel insights into the mechanisms underlying Tfh cell and GC maintenance.
Talk 8: Maintenance of GC Tfh Response in Humans
Professor Hideki Ueno, Graduate School of Medicine, Kyoto University, Japan
Immunological memory is fundamental to protect the host from a re-infection of the pathogen. The maintenance of humoral memory is mediated by long-lived plasma cells and memory B cells. Their development requires helper signals, including CD40, provided by T follicular helper (Tfh) cells in germinal centers (GCs). GC-Tfh cells participate in the selection of high-affinity B cells and their differentiation into long-lived plasma cells and memory B cells and therefore are fundamental for the generation of durable humoral responses.
Memory Tfh cells play essential roles in the secondary Ab response and provide help to memory B cells and naïve B cells. Memory Tfh cells are present in blood circulation as well as lymphoid organs. The molecular mechanism required for the development of memory Tfh cells remains poorly defined. In my seminar, I will provide evidence that transcription factor Tox2 is important for the maintenance of GC Tfh cells both in humans and mice. I will also share our recent analysis on single cell RNAseq data of human tonsillar CD4+ T cells regarding the plasticity of human GC Tfh cells.
Additional Q&A for talks 6-8 and discussion