Antigen specific B cell responses
Group leader: Prof Marieke van Ham PhD
Our research focuses on the role of antigen-specific B cells in B-T cell interactions and humoral immunity. We previously demonstrated that antigen-specific B cells phagocytose particles and bacteria. We now investigate how this leads to B cell differentiation, class switching and antibody formation. We make use of infection and cancer models and use tetanus toxoid and the therapeutic antibody adalimumab to investigate antibody response against non-infectious antigens upon frequent antigen re-encounter (hyper-immunization or repeated treatment).
Antigen-specific B-T cell interactions and antibody production
Phagocytosis of Salmonella typhimurium by B cells leads to efficient CD4+ T helper (Th) cell activation, which in turn enhances Salmonella-specific antibody formation. B cells regulate CD4+ T cell polarization. During antigen recall, Th17 cells are activated. The induction of Th17 from naive CD4+ T cells in humans is still unclear. We demonstrated that, compared to classical CD28 costimulation, alternative costimulation via CD5 is superior for human Th17-priming (Figure 1). We showed that this depends on elevation of pSTAT3 and IL-23 receptor expression. Whereas in mice Th17 cells coproduce IL-21, in humans other Th subsets produce IL-21. As IL-21 is a key factor for B cell help, we are currently studying if and how B cells induce IL-21 Th polarization.
Figure 1: FACS-sorted naive CD4+CD45RA+CD45RO– T cells were stimulated via coated CD3/CD28 or CD3/CD5 antibodies under Th17 polarizing conditions (IL-23, IL-1β, IL-6, TGF-β and anti-IFN-γ). Left: Intracellular levels of IFN-γ and IL-17A levels were measured at day 11, after 5 hrs of re-stimulation with PMA, ionomycin and BFA. FACS plots shown are from one representative of 18 different donors Right: IFN-γ and IL-17 levels were measured by ELISA at day 11, after 24 hrs of re-stimulation with a CD3-specific Mab (1 μg/ml) and PdBu (50 μM). Data are shown as a mean of 19 individual experiments with different donors.
B-T cell interactions and antibody production upon hyper-immunization
In 2011 we focused on the formation of anti-tetanus toxoid (TT) antibodies in voluntary donors that are frequently boosted to obtain sufficient antibody titers. We established a
well-defined cohort of donors with a confirmed history of frequent re-immunizations and documented specific antibody titers over 5-10 years, to investigate hyper-immunization effects on long-term humoral immunity. We performed frequent antibody titer measurements within one year of follow-up to also investigate effects on short-term antibody responses. In vitro B-T cell co-cultures indicate that frequent TT boosting induces CD4+ T cell subsets that are specialized in supporting antibody formation.
Antigen presentation in leukemia.
We are studying the regulation of MHC class I and II-Ag presentation in leukemia to determine whether tumor cells target these pathways to escape from immune recognition. In collaboration with Dr Arjan van de Loosdrecht (Department of Hematology, VUmc), we demonstrated in 2010 that leukemic blasts use the MHC I chaperone TAP for peptide loading of MHC class II. In 2011 we identified another form of cross-over of MHC class I and II regulation in acute myeloid leukemia. CLIP, an essential chaperone intermediate of MHC II presentation, also binds to MHC class I molecules and may lead to aberrant MHC I antigen presentation.
- Souwer Y, de Wit J, Griekspoor A, Martinoli C, Zagato E, Janssen H, Jorritsma T, Bar-Ephraïm YE, Rescigno M, Neefjes J, van Ham SM. Selective infection of antigen-specific B lymphocytes by Salmonella mediates bacterial survival and systemic spreading of infection. PLoS One 2012; 7:e50667.
- Souwer Y, de Wit J, Muller FJ, Klaasse Bos H, Jorritsma T, Kapsenberg ML, de Jong EC, van Ham SM. Priming of human naive CD4+ T cells via CD5 costimulation requires IL-6 for optimal Th17 development. Blood 2012; 119:4812.
- Van Luijn MM, van de Loosdrecht AA, Lampen MH van Veelen PA, Zevenbergen A, Kester MG, de Ru AH, Ossenkoppele GJ, van Hall T, van Ham SM. Promiscuous binding of invariant chain-derived CLIP peptide to distinct HLA-I molecules revealed in leukemic cells. PLoS One 2012; 7:e34649.
- De Wit J, Souwer Y, van Beelen AJ, de Groot R, Muller FJ, Klaasse Bos H, Jorritsma T, Kapsenberg ML, de Jong EC, van Ham SM. CD5 costimulates for stable human Th17 development by promoting IL-23R expression and sustained STAT3 activation. Blood 2011; 118:6107-14.