Bosma, A;
(2013)
Cross-talk between invariant natural killer T cells and B cells under homeostatic conditions and during inflammation.
Doctoral thesis , UCL.
Abstract
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.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | Cross-talk between invariant natural killer T cells and B cells under homeostatic conditions and during inflammation |
| Event: | UCL |
| Additional information: | UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of) |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1452790 |
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