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Dr Nicola Jackson

Research Interests

Salmonella enterica serovar Typhimurium (S. Typhimurium) is an intracellular pathogen capable of infecting both professional and non-professional antigen-presenting cells. Salmonella has evolved a variety of virulence strategies to evade immune surveillance and maintain its intracellular niche within the Salmonella-containing vacuole (SCV). Of critical importance to virulence are the Salmonella Pathogenicity Islands (SPI) that encode type III secretion systems (T3SS) capable of injecting bacterial effector proteins into host cells.

Recognition of peptide-MHC-II complexes by CD4+ T cells is central to the development of an adaptive immune response. Control of Salmonella infection requires MHC-II restricted CD4+ T cell responses; however, development of adaptive immunity to Salmonella infection is delayed and inefficient. Distinct peptide-MHC-II complexes, recognised by Type A and Type B CD4+ T cell subsets, are generated when antigen is loaded in different intracellular compartments.  Conventional Type A T cells recognize their peptide epitope regardless of the route of processing, whereas unconventional Type B T cells only recognise exogenously supplied peptide.  Type B T cells are implicated in autoimmune conditions and may break tolerance by escaping negative selection.

We are interested in how Salmonella influences MHC-II restricted antigen presentation to different CD4+ T cell subsets. Cells harbouring replicating Salmonella exhibit elevated MHC-II polyubiquitination and reduced MHC-II surface expression (Lapaque N et al. 2009 and Mitchell E et al. 2004).  We have shown that Salmonella differentially influences presentation of antigen to Type A and B T cells.  Infection of BMDCs with S. Typhimurium reduced presentation of antigen to Type A T cells but enhanced presentation of exogenous peptide to Type B T cells.  Reduced MHC-II surface expression in S. Typhimurium-infected BMDCs correlated with reduced antigen presentation to Type A T cells.

Given that Type B T cells are implicated in autoimmunity and Salmonella infection is implicated in autoimmune conditions such as reactive arthritis, it is conceivable that Salmonella-induced polarisation of antigen presentation towards a Type B response may predispose to autoimmunity.  Studies to evaluate the role of Type B T cells in infection and autoimmunity are ongoing in the Trowsdale laboratory.

Keywords

autoimmunity ; antigen processing ; host-pathogen interaction ; bacterial infections ; antigen presentation ; ubiquitin

Key Publications

Jackson NP, Kang YH, Lapaque N, Janssen H, Trowsdale J, Kelly AP. Salmonella polarises peptide-MHC-II presentation towards an unconventional Type B CD4(+) T-cell response. Eur J Immunol. 2013 Volume 43, Issue 1, January 2013 doi: 10.1002/eji.201242983. [Epub ahead of print]
Langley R, Patel D, Jackson N, Clow F, Fraser JD. Staphylococcal superantigen super-domains in immune evasion. Crit Rev Immunol. 2010; 30(2): 149-65

Laursen NS, Gordon N, Hermans S, Lorenz N, Jackson N, Wines B, Spillner E, Christensen JB, Jensen M, Fredslund F, Bjerre M, Sottrup-Jensen L, Fraser JD, Andersen GR. Structural basis for inhibition of complement C5 by the SSL7 protein from Staphylococcus aureus. Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3681-6.