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Title: Cross-talk between invariant natural killer T cells and B cells under homeostatic conditions and during inflammation
Author: Bosma, A.
Awarding Body: UCL
Current Institution: University College London (University of London)
Date of Award: 2013
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B cells perform several immunological functions, including the production of antibodies, release of cytokines and presentation peptide or lipid-antigen respectively to T or invariant natural killer T (iNKT) cells. Patients with systemic lupus erythematous (SLE) display dysregulated B cell responses and reduced peripheral iNKT cell frequencies. The significance of these defects and how they relate to SLE pathogenesis remains elusive. I examined the role of B cells in the maintenance of iNKT cells in healthy individuals and SLE patients. I report that B cells are essential for iNKT cell expansion and activation in healthy individuals but fail to exert a similar effect in SLE patients. Defective B cell-mediated iNKT cell stimulation in SLE was associated with rapid internalization and reduced CD1d surface expression on SLE B cells compared to healthy B cells, a defect that could be recapitulated in healthy B cells after simultaneous stimulation with interferon-alpha and anti-immunoglobulin. Strikingly, iNKT cell number and function were restored in SLE patients responding to anti-CD20 treatment upon normalization of CD1d levels exclusively in repopulated immature B cells. Furthermore, I demonstrated that B cells are essential for the maintenance of iNKT cells during experimental arthritis. Whereas alphaGalCer treatment ameliorated arthritis in wild-type mice, alphaGalCer treatment had no effect in arthritic B cell deficient mice. Amelioration of arthritis was paralleled with the proliferation of iNKT cells and a skew towards a Th2-like cytokine milieu. Further, I show that iNKT cells are necessary for the differentiation of regulatory B cells (Bregs). Whereas WT Bregs were capable of suppressing arthritis, Bregs isolated from iNKT cell deficient mice failed to exert the same effect despite producing IL-10. Impaired Breg suppression was associated with a potential trafficking defect. These results suggest that B cell-iNKT cell cross-talk is pivotal for the maintenance of tolerance in both human and mice.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available