T cell/B cell collaboration in autoimmunity

Regulatory T cells prevent the emergence of autoantibodies and excessive IgE but the precise mechanisms are unclear. Here we show that BCL6-expressing Tregs, known as follicular regulatory T (Tfr) cells produce abundant amounts of a neuropeptide that targets B cells. Mice lacking Tfr cells or the Tfr-derived neuropeptide in Foxp3-expressing cells accumulated early plasma cells in germinal centers (GCs) and developed autoantibodies against histones and tissue-specific self-antigens. Upon immunization, these mice also produced increased serum IgE and IgG1. We show that the Tfr-derived neuropeptide is taken up by B cells, causes phosphorylation of numerous proteins and dampens IgE class switching. The Tfr-derived neuropeptide reduced differentiation of mouse and human GC B cells into plasma cells, downregulated BLIMP-1 and upregulated BCL6. Administration of the neuropeptide to Tfr-deficient mice prevented the accumulation of early plasma cells in GCs. Production of this neuropeptide by Tfr cells emerges as a central mechanism to suppress B cell-driven autoimmunity and IgE-mediated allergies. 

Professor Carola Vinuesa, John Curtain School of Medical Research, The Australian National University

Professor Carola Vinuesa, John Curtain School of Medical Research, The Australian National University

Carola Vinuesa was born in Spain and obtained a medical degree at the University Autonoma of Madrid. She undertook specialist clinical training in the UK and in 2000 was awarded a PhD by the University of Birmingham. A year later she was the recipient of a Wellcome Trust International Travelling prize Fellowship to do postdoctoral work at The John Curtin School for Medical Research in The Australian National University. Since 2006 she has been a group leader. She has been the recipient of several prestigious awards including the Science Minister’s Prize for Life Scientist of the year (2008), the Gottschalk Medal of the Australian Academy of Sciences (2009). She was elected as a Fellow of the Australian Academy of Science (AAS) in 2015, and the Australian Academy of Health and Medical Sciences (AAHMS) in 2020. She is currently Professor of Immunology at the Australian National University and Director of the Centre for Personalised Immunology (CPI), an NHMRC Centre for Research Excellence.

Antibody affinity maturation depends on germinal center (GC) positive selection of rare clones that acquire higher-affinity B cell receptors via somatic hypermutation, present more antigen to follicular helper T (Tfh) cells and, consequently, receive more contact-dependent T-cell help. As Tfh and GC B cells do not maintain long-lasting contacts in the chaotic GC environment, it is unclear how sufficient T-cell help is cumulatively focused onto those rare clones. Here we show that, upon receipt of CD40 stimulation, GC B cells upregulate chemokine CCL22 and to a lesser extent CCL17. By engaging CCR4 on Tfh cells, CCL22 and CCL17 can attract attention to a B cell by multiple helper cells from a distance, thus increasing the chance of productive help. In a GC response, B cells that acquire higher antigen-binding affinities express higher levels of CCL22, and higher levels of CCL22 expression highlight GC B cells of higher affinities. Acute increase or blockade of Tfh help rapidly increase or decrease CCL22 expression by GC B cells. Therefore, a chemokine-based intercellular reaction circuit translates the amount of T-cell help individual B cells recently receive to their subsequent ability to attract more help. When CCL22 and CCL17 are ablated in B cells, GCs form but do not efficiently mature in affinity. When competing with wildtype B cells in the same reaction, those lacking CCL22 and CCL17 are disadvantaged in acquiring T-cell help to maintain GC participation or develop into bone-marrow plasma cells. Therefore, a chemokine-mediated mechanism highlights affinity-improved B cells for Tfh cells to focuses attention from a distance. This ensures efficient positive selection despite the chaotic crowding of competitors.

Dr Hai Qi, Tsinghua University, China

Dr Hai Qi, Tsinghua University, China

Dr Qi is a Professor in Immunology at Tsinghua University. His group studies humoral immune regulation and germinal center biology. His work has made important contributions to our understanding of how antigen-specific and bystander interactions between T and B cells are molecularly regulated, how cellular dynamics underlying the germinal center is organized to support positive selection, and how cell fate decisions during the germinal center reaction are made. More recently, his group has made important advances in mechanistic understanding of how sexual dimorphism is orchestrated in B-cell immunity and how brain can directly control antibody responses. Dr Qi is an HHMI International Scholar and has been recognized by numerous awards, including an AAI-BD Investigator Award.

Follicular helper T cells (Tfh) cells shape the germinal center (GC) response by delivery of contact-dependent signals and cytokines, including IFN-γ and IL-21. The contribution of these discrete extrinsic signals to the dysregulation of GC B cells in lupus is unclear. In lupus, by contrast to acute viral challenge, GCs persist as disease progresses, and transcriptional analysis of lupus-Tfh cells at different stages of disease revealed an evolving gene expression profile that corresponded to disease progression. However, Tfh cells from early and chronic GCs continued to robustly co-produce both IL-21 and IFN-γ with ongoing genesis of IgG2 autoantibody production, necessary for immune complex-derived glomerulonephritis. Additionally, CD11c- and Tbet-expressing age-associated B cells (ABCs) comprise a distinct B-cell subset that contributes to autoantibody production. Unlike Tfh and GC B cells, we show that ABCs accumulate as disease progresses in lupus-prone mice. However, their developmental reliance upon T cell help and relationship to GC B cells are unclear. To this end, we examined ABCs in a murine acute LCMV infection model, finding that Tfh, not T helper 1, cells drove their differentiation prior to and independent of the GC response. ABCs rarely overlap with GC B cells in phenotype, transcriptional profile, and clonality, with their development often diverging from that of GC B cells. These data indicate that ABCs in response to viral infection are predominantly generated independent of the GC response, yet their development is dependent upon help delivered by Tfh cells.

Dr Jason Weinstein, Rutgers New Jersey Medical School, USA

Dr Jason Weinstein, Rutgers New Jersey Medical School, USA

Dr Weinstein is an assistant professor and Chancellors’ Scholar at Rutgers University. He has a long-held interest in immunology, particularly in understanding T-B collaboration in normal and autoimmune responses. His graduate work focused on understanding autoreactive B cell generation and function in ectopic lymphoid tissue found in various autoimmune diseases. Dr Weinstein completed his postdoctoral training at Yale University, assessing the developmental requirements of T follicular helper (Tfh) cells and their regulation of germinal center B cells in both infection and autoimmunity.

In addition to these cellular studies, he used genomic approaches to identify novel Tfh-cell specific enhancers from chronically inflamed tonsils. Dr Weinstein’s lab combines advanced approaches in cellular immunology and genomics to investigate the dynamic genetic regulation and function of pathogenic T and B cells from early to advanced autoimmunity in comparison to those following pathogen challenge.

T cell- B cell interactions often take place within target tissues in chronic autoimmune conditions, yet T cell populations that drive these peripheral T-B cell interactions remain difficult to define. Rheumatoid arthritis synovium provides a valuable test case, where the synovium is often studded with T cell-B cell aggregates. We found that rheumatoid synovium contains a highly expanded population of PD-1hi CXCR5- CD4+ T cells that express high levels of IL-21 and CXCL13 and resemble Tfh cells cytometrically and transcriptomically. However, this PD-1hi CXCR5- cell population differed from Tfh cells in particular in migratory programs, expressing a distinct set of chemokine receptors including CCR2 and CCR5. We called these cells T peripheral helper (Tph) cells to capture the idea that they would provide help to B cells in inflamed peripheral tissues rather than within lymphoid follicles. We found that Tph cells are also highly expanded in the circulation of patients with lupus and that they depend on expression of MAF to produce IL-21 and stimulate B cell responses in vitro. Current ongoing work aims to identify Tph cells in murine models of lupus and to evaluate their contribution to pathologic B cell responses in vivo.   

Dr Deepak Rao, Harvard University, USA

Dr Deepak Rao, Harvard University, USA

Dr Rao is a rheumatologist and immunologist at Brigham and Women’s Hospital and Assistant Professor of Medicine at Harvard Medical School. He serves are co-director of the Human Immunology Center and scientific co-director of the Single Cell Genomics Core at BWH. His work focuses on identifying the immune cell phenotypes and pathways that characterize distinct autoimmune diseases. Using high dimensional analyses including mass cytometry and RNA-seq of samples from patients with rheumatoid arthritis and lupus, his group described a population of ‘T peripheral helper’ cells that is pathologically expanded in multiple autoantibody-associated conditions. His ongoing work focuses on defining regulators of human Tph and Tfh cell function, and utilizing Tph and Tfh cell phenotypes as clinical metrics of autoimmune activation. He has received a Career Award for Medical Scientists from the Burroughs Welcome Fund and a Clinical Scientist Development Award from the Doris Duke Charitable Foundation to support these efforts.

Type 1 diabetes (T1D) is an autoimmune disease that typically starts in childhood and results in the destruction of insulin-producing beta cells in the pancreas. Although type 1 diabetes is primarily considered to be a T-cell mediated disease, B cells clearly participate in the autoimmune process. For example, autoantibodies recognizing pancreatic islet antigens commonly appear in circulation before the onset of the disease. Using blood samples from a longitudinal follow-up cohort, we have analyzed the frequency of circulating T follicular helper (Tfh) and T peripheral helper (Tph) cells in children at different stages of T1D development. We have observed that both activated circulating Tfh cells (defined as CD4+CXCR5+PD-1+ICOS+) as well as Tph cells (CD4+CXCR5-PD1hi) are increased in the blood of children with newly diagnosed T1D, especially in those individuals positive for multiple autoantibodies. These cell subsets were also shown to be increased in frequency in autoantibody-positive at-risk individuals who later progressed to T1D. Our results suggest that an increase in circulating Tfh and Tph cells is associated with T1D onset and they could therefore potentially be used as biomarkers of disease progression. Moreover, our results lend support to the idea that Tfh/Tph activation pathways can be potential targets for the immunotherapy of T1D.

Professor Tuure Kinnunen, University of Eastern Finland

Professor Tuure Kinnunen, University of Eastern Finland

Tuure Kinnunen received his MD in 2005 and PhD in immunology in 2007 from the University of Kuopio, Finland. Following a post-doctoral fellowship at Yale University in 2010-2011, his main research focus has been to study immunological changes during the development of type 1 diabetes using blood samples from a longitudinal follow-up cohort of children at a high risk of developing type 1 diabetes. These studies have particularly focused on the phenotype and function of regulatory T (Treg) cells and follicular T helper (Tfh) cells. He is currently Professor of Clinical Microbiology and Immunology at the University of Eastern Finland.

The lung is one of the largest barrier organs and not only involved in pulmonary infections but also different chronic inflammatory interstitial lung diseases. T and B cells are frequently found in inflammatory infiltrates. We recently showed in a mouse lung inflammation model that active T cell / B cell cooperation can take place directly in the lung tissue. A special population of T follicular helper- (Tfh-) like cells drives the differentiation of lung-infiltrating B cells into antibody-producing cells. Tfh-like cells (also known as peripheral T helper cells (Tph)) lack the classical Tfh markers CXCR5 and Bcl-6 but provide potent B cell help by production of IL-21 and high expression of CD40L. T/B cooperation in the lung takes places in unstructured, non-ectopic peribronchial infiltrates but nevertheless results in efficient B cell receptor hypermutation. 

We now identified a similar population of Tfh-like cells in inflamed lungs from sarcoidosis patients. This systemic inflammatory disease was previously thought to be a primarily Th1 and macrophage-driven disease. However, lung-infiltrating T cells also produce large amounts of IL-21 and provide potent B cell help in vitro. Large clusters of T and B cells can be found in the lung tissue and these infiltrates are typically surrounded by IgA-producing plasma blasts, indicating their local generation in the lung. These findings highlight the role of T cell / B cell cooperation as a novel pathomechanism for sarcoidosis.

Professor Dr Andreas Hutloff, University of Kiel, Germany

Professor Dr Andreas Hutloff, University of Kiel, Germany

Professor Dr Andreas Hutloff studied Biochemistry at the University of Hamburg and did his PhD at the Robert Koch Institute in Berlin. Very recently he moved with his group from the German Rheumatism Research Centre Berlin to the University Hospital Schleswig-Holstein in Kiel, Germany. Since identification of the T cell costimulator ICOS in 1999, his main interest has been the molecular regulation of T follicular helper cells and their interaction with B cells. His group recently identified a novel population of Tfh-like cells (also known as Tph cells), which drive B cell differentiation in chronically inflamed non-lymphoid tissues.

While the spectrum of coronavirus disease 2019 (COVID-19) ranges from asymptomatic infection to severe and sometimes fatal, it remains unknown what determines divergent clinical trajectories among patients. COVID-19 patients quickly develop antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but these antibodies may be protective or pathogenic. Protective antibodies neutralize virus or contribute to viral clearance by activating Fc receptor-expressing cells, while pathogenic antibodies can contribute to hyperinflammatory responses or even enhance infection by SARS-CoV-2. Studies of antibody responses in COVID-19 patients demonstrate that severe disease is associated with impaired T follicular helper (Tfh) cell and germinal center responses, suggesting that Tfh-independent pathways of antibody induction could contribute to COVID-19 severity. Using a murine model of SARS-CoV-2 infection, we defined the features of Tfh cell-dependent and Tfh cell-independent antibody responses. Tfh cell help was required for long-lived antibody responses to SARS-CoV-2. Tfh cell-dependent antibodies also demonstrated increased recognition of spike S2 fusion peptide-derived epitopes. Furthermore, antibodies that developed in the absence of Tfh cell help exhibited altered Fc isotype profiles. Ultimately, we aim to identify the cellular pathways and antibody features that mediate SARS-CoV-2-induced disease severity as well as define a new paradigm in which different CD4+ T cell subsets guide the production of protective versus pathogenic antibodies to viruses.

Dr Stephanie Eisenbarth, Yale University School of Medicine, USA

Dr Stephanie Eisenbarth, Yale University School of Medicine, USA

Dr Stephanie Eisenbarth is an Associate Professor in the Departments of Laboratory Medicine, Immunobiology and the Section of Rheumatology, Allergy & Immunology at Yale University School of Medicine. Her research focuses on how dendritic cells, B cells and T cells interact to induce tailored adaptive immune responses, both in the context of productive immunity to vaccines and infection, but also maladaptive responses to allergens and transplanted alloantigens. Dr Eisenbarth practices clinical pathology at Yale New Haven Hospital with a focus on immune-mediated disorders including autoimmunity, immunodeficiency syndromes and allergic disease.