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Regulation of antigen specific B and CD4 T cell responses

Research lines

Regulation of human T cell-dependent B cell differentiation and IgG formation

IgG secreting B cells are essential for immunity against pathogens, but also lead to pathology when formed against self-antigens or allo-determinants upon blood transfusion. We investigate how the three signals for IgG B cell differentiation (BCR signalling, CD40 costimulation and T cell-derived cytokines) regulate antigen-specific IgG formation and PC formation. We were the first to demonstrate that recognition of particulate antigen or bacteria by the BCR leads to phagocytosis and optimized T cell-mediated IgG formation. Recently we established a robust system for naïve B cell differentiation into IgG-secreting PC. Using scRNAseq we identified the first linear Bn->PC differentiation pathway known so far and novel cell surface differentiation markers. Besides we established CRISPR-Cas9 technology in primary human B cells to unravel the role of newly identified transcription factors of B->PC differentiation.

Follicular T helper (Tfh) cells are crucial for B cell help, among others via secretion of IL-21. Knowledge of factors that control human Tfh development is limited. Our recent experiments showed that human antigen-specific B cells strongly drive Tfh priming and reactivation, in contrast to DCs that induce Th1 polarization. B cells thus seem to direct CD4 T cell differentiation towards optimal help for antibody responses. B cell-depleting therapies demonstrated that B cells also regulate CD4 T cell responses in general through unknown mechanisms. We identified two pathways via which B cells regulate CD4 effector T cell formation and control the balance between central and effector memory CD4 T cell formation. We are currently unraveling these regulatory pathways in detail.

As analyses of regulatory networks is of importance to tackle our research well, we will embed bio-informatics and systems biology for analyses of bulk/scRNAseq, proteomics and BCR/TCR-clonality data.

Identification of early markers and regulators of B cell differentiation is much desired to prevent alloantibody formation (eg RhD in pregnant women, RBC and platelet transfusions), to intervene against autoantibodies (MS/vasculitis/pemphigus/SLE/RA) or to enhance desired IgG-formation (hyperimmunisation/vaccination) within the national Target to B consortium we study B cell differentiation in a disease-overarching approach.

Regulation of adaptive immune responses by platelets

Platelets are typically known for their role in primary hemostasis but are increasingly acknowledged for their role in modulating immune responses by chemokine and cytokine release upon activation. Furthermore platelets can express adhesion molecules involved in interactions with immune cells. Platelets have been shown to affect the maturation phenotype of dendritic cells (DC), but it is unknown if this also changes the further DC mediated adaptive immune response or B cells responses. We therefore investigate the effect of platelets on monocyte-derived DC maturation and their ability to stimulate antigen-specific T cells. In addition, since platelets express high level of CD40L, we investigate the effect of platelets on B cell differentiation and antibody production.

Immunomonitoring of antigen-specific T and B cell responses

Immunomonitoring assays (https://www.sanquin.org/products-and-services/immunomonitoring-services/index) are becoming increasingly important now there is a rapid increase in development of therapies that target or affect the immune system. It can provide proof of mechanism for drugs in development, exploratory additional data during clinical trials and help select relevant patients. Important steps have been made in the field of immunotherapy, where therapy directly depends on the action of the immune system to achieve efficacy. The current trend is development of ‘tailor-made’ therapies, where patients will receive treatments that are best suited to fit their specific needs. Part of the immune therapies are cell therapies with in vitro cultured autologous immune cells, such as antigen loaded DC, TILs, CAR-T or Treg. In general it is aimed to induce antigen-specific responses in the patients, therefore the characterization of CD4+ T cells is crucial for understanding their role in immunotherapeutic approaches such as vaccinations or tolerizing therapies, both for their helper function in CD8 T cell responses as their essential role in the development of antigen-specific B cell responses and antibodies. Development of sensitive assays to monitor antigen-specific immune responses is there for one of our research focusses. In the EU H2020 consortium RESTORE (www.h2020restore.eu) we study the effect of treatment of MS patients with MS peptide-loaded tolerance inducing DC on antigen-specific T and B cell responses. In the national DC4Balance consortium we focus on the analysis of antigen-specific immune responses upon DC therapy through identification of antigen-specific CD4 T (and B) cells via TCR/BCR clonality analyses and functional assessment of effects of therapy on these cells.

We collaborate closely with the group of Theo Rispens to delineate structure-function relationships of antibodies (Structure and function of antibodies) and with the group of Robbert Spaapen to perform genomic screens (Antigen presentation and immunotherapy).

Key publications

  • Verstegen NJM, Unger PA, Walker JZ, Nicolet BP, Jorritsma T, van Rijssel J, Spaapen RM, de Wit J, van Buul JD, Ten Brinke A, van Ham SM. Human B Cells Engage the NCK/PI3K/RAC1 Axis to Internalize Large Particles via the IgM-BCR. Front Immunol. 2019 Mar 13;10:415. doi: 10.3389/fimmu.2019.00415
  • Lighaam LC, Unger PA, Vredevoogd DW, Verhoeven D, Vermeulen E, Turksma AW, Ten Brinke A, Rispens T, van Ham SM. In vitro-Induced Human IL-10+ B Cells Do Not Show a Subset-Defining Marker Signature and Plastically Co-express IL-10 With Pro-Inflammatory Cytokines. Front Immunol. 2018 Sep 5;9:1913. doi: 10.3389/fimmu.2018.01913
  • Unger PA, Makuch M, Aalbers M, Derksen NIL, Ten Brinke A, Aalberse RC, Rispens T, van Ham SM. Repeated vaccination with tetanus toxoid of plasma donors with pre-existing specific IgE transiently elevates tetanus-specific IgE but does not induce allergic symptoms. Clin Exp Allergy. 2018 Jan 31. [Epub ahead of print]
  • Saris A, Peyron I, van der Meer PF, Stuge TB, Zwaginga JJ, van Ham SM, Ten Brinke A. Storage-Induced Platelet Apoptosis Is a Potential Risk Factor for Alloimmunization Upon Platelet Transfusion. Front Immunol. 2018 Jun 5;9:1251. doi: 10.3389/fimmu.2018.01251.
  • Ten Brinke A, Marek-Trzonkowska N, Mansilla MJ, Turksma AW, Piekarska K, Iwaszkiewicz-Grześ D, Passerini L, Locafaro G, Puñet-Ortiz J, van Ham SM, Hernandez-Fuentes MP, Martínez-Cáceres EM, Gregori S. Monitoring T-Cell Responses in Translational Studies: Optimization of Dye-Based Proliferation Assay for Evaluation of Antigen-Specific Responses. Front Immunol. 2017 Dec 21;8:1870.
  • de Wit J, Jorritsma T, Makuch M, Remmerswaal EB, Klaasse Bos H, Souwer Y, Neefjes J, ten Berge IJ, van Ham SM. Human B cells promote T-cell plasticity to optimize antibody response by inducing coexpression of T(H)1/T(FH) signatures. J Allergy Clin Immunol. 2015 Apr;135(4):1053-60
  • Lighaam LC, Vermeulen E, Bleker Td, Meijlink KJ, Aalberse RC, Barnes E, Culver EL, van Ham SM, Rispens T. Phenotypic differences between IgG4+ and IgG1+ B cells point to distinct regulation of the IgG4 response. J Allergy Clin Immunol. 2014 Jan;133(1):267-7