fig004nwb: A proposed model for EtxB-mediated immunomodulation

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A proposed model for EtxB-mediated immunomodulation

Robert J. Salmond, Jeffrey A. Luross and Neil A. Williams

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Figure 4. A proposed model for EtxB-mediated immunomodulation. Interaction of the B subunit of the Escherichia coli enterotoxin Etx with its receptor ganglioside G_M1 modulates the activation of antigen-presenting cells (APCs), T cells and B cells within sites local to delivery. Cytokine production by APCs is modulated, leading to enhanced production of interleukin 10 (IL-10), with a concomitant suppression of IL-12 synthesis. In this way, the major cytokine that drives T helper 1 (Th1) differentiation is blocked in favour of the production of a factor able to promote T regulatory (Treg)-cell differentiation (e.g. see Refs 35, 68). Some local CD8⁺ T cells undergo apoptosis (Ref. 44) and are thus unavailable as a potential source of interferon g (IFN-g) that might otherwise favour Th1 differentiation. B cells are polyclonally activated, a process that might involve them further in antigen presentation and thus favour the induction of Th2 immunity. In addition, this would aid in promoting the response of B cells to admixed antigens and would initiate a stronger antibody response. Taken together, the changes to the local microenvironment induced by EtxB would favour the differentiation of T cells away from the Th1 pathway and, instead, favour the generation of Treg- and Th2-cell populations. Th2 cells would favour the generation of an IgA antibody response, which might be influenced by the presence of transforming growth factor b (TGF-b) from Treg cells and B cells. Both Th2 cells and Treg cells would act to prevent the immunopathological Th1 response in autoimmune disease (Refs 33, 34). In the presence of admixed vaccine antigens, Th2 cells would favour the observed mucosal and IgG1 response, an effect that might be further influenced by certain types of Treg cells (fig004nwb).

References cited in Figure 4

33 Williams, N.A. et al. (1997) Prevention of autoimmune disease due to lymphocyte modulation by the B-subunit of Escherichia coli heat-labile enterotoxin. Proc Natl Acad Sci U S A 94, 5290-5295, PubMed

34 Luross, J.A. et al. (2002) Escherichia coli heat-labile enterotoxin B subunit prevents autoimmune arthritis through induction of regulatory CD4+ T cells. Arthritis Rheum 46, 1671-1682, PubMed

35 Shevach, E.M. (2000) Regulatory T cells in autoimmmunity. Annu Rev Immunol 18, 423-449, PubMed

44 Elson, C.O. et al. (1995) Morphologic and functional alterations of mucosal T cells by cholera toxin and its B subunit. J Immunol 154, 1032-1040, PubMed

68 Asseman, C. et al. (1999) An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med 190, 995-1004, PubMed

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