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Title: Inhibition of T-cell responses by microbes and immune cells
Author: Preciado-Llanes, Lorena
ISNI:       0000 0004 2745 4467
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2013
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Some antigens can induce B-cell activation and antibody production without 'T cell help' and hence are called T-independent (TI) antigens. Similarly to bacterial capsular polysaccharides, anti- IgDconjugated dextran (α-δ-DEX) is a TI type 2 mimic which stimulates B lymphocytes by crosslinking of numerous B-cell receptor molecules. This thesis demonstrates that α-δ-DEX-activated B-cells directly inhibit TCR-induced CD4+ T-cell proliferation and activation in vitro. Experiments performed with purified cell populations excluded the possibility of α-δ-DEX acting directly on CD4+ T lymphocytes and confirmed that B lymphocytes exposed to α-δ-DEX for a period of 24 hours become activated and acquire a suppressive phenotype. Interestingly, these suppressor Bcells appear to be effective even when they are present at numbers below the physiological T:B ratio. Although the exact mechanism of action remains obscure, this is the first evidence of TI type 2 antigen activated B-cells mediating inhibition of activation and proliferation of helper T lymphocytes. Neisseria meningitidis is a bacterium which rarely causes invasive disease and sepsis, but perpetuates colonisation in the nasopharynx by avoiding immune recognition and killing. Because several N. meningitidis constituents are TI type 2 antigens and/or provide second signals to B-cells via TLRs, it was hypothesized that paraformaldehyde fixed meningococcus could exert immunomodulatory properties. A deep suppression of CD4+ T-cell responses occurred when aCD3-stimulated PBMCs where incubated with small meningococci counts (ratios between 0.1 to 10:1 bacteria per cell). A clear TH1 cytokine profile and IL-10 secretion was observed in supernatants from these cultures. Interestingly, outer membrane vesicles (OMVs) from N. meningitidis and N. lactamica replicated the suppression phenomenon induced by the whole organism. Bacterial capsule, lipooligosaccharides and Opa are not responsible for the suppressive effect. Depletion of B-cells, monocytes or NK cells does not reverse the meningococcus-mediated inhibition in PBMC cultures. Several bacterial components stimulate nitric oxide (NO) production, however N. meningitidis can counteract the bactericidal effect of reactive nitrogen intermediates by a partial denitrification pathway. Since NO is also produced as a result of TCR engagement, it was investigated whether NO donation or inhibition could influence CD4+ T-cell responses. A novel specific eNOS inhibitor (Cavtratin) derived from the caveolin-1 structure was tested for the first time in PBMC cultures. Cavtratin concentrations of 10 and 15 μM increases proliferation of CD4+ T lymphocytes and reduce the percentage of cell death in the PBMC culture after anti-CD3 stimulation.
Supervisor: Read, Robert C. ; Heath, Andrew W. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available