Low-avidity recognition by CD4(+) T cells directed to self-antigens
ABSTRACT Self-reactive T cells populate the peripheral immune system, and likely form the reservoir from which autoreactive cells are derived. We analyzed a panel of self and non-self peptides presented by HLA-DR4, a class II molecule associated with autoimmunity, by immunization of mice transgenic for HLA-DR4. Significant structural avidity for T cell recognition, as measured by MHC class II tetramer binding to CD4(+) T cells was only observed in mice immunized with the non-self antigens. T cell hybridomas were generated from mice immunized with the naturally processed self-peptide hGAD65 (552-572) and also from mice immunized with an influenza-derived non-self epitope (HA 306-318). T cells specific for the self peptide failed to bind tetramers and exhibited low functional avidity as measured by the peptide concentration required to reach half-maximum proliferation values. In contrast, T cells specific for the non-self HA (306-318) peptide exhibited high structural and functional avidity profiles. As recently described in studies of murine CD8(+) T cell function, the predominance of low avidity recognition of self-peptide epitopes may be a characteristic feature of CD4(+) T cells responding to autoantigens.
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ABSTRACT: Microorganisms induce strong immune responses, most of which are specific for their encoded antigens. However, microbial infections can also trigger responses against self antigens (autoimmunity), and it has been proposed that this phenomenon could underlie several chronic human diseases, such as type 1 diabetes and multiple sclerosis. Nevertheless, despite intensive efforts, it has proven difficult to identify any single microorganism as the cause of a human autoimmune disease, indicating that the 'one organism-one disease' paradigm that is central to Koch's postulates might not invariably apply to microbially induced autoimmune disease. Here, we review the mechanisms by which microorganisms might induce autoimmunity, and we outline a hypothesis that we call the fertile-field hypothesis to explain how a single autoimmune disease could be induced and exacerbated by many different microbial infections.Nature Reviews Microbiology 12/2003; 1(2):151-7. DOI:10.1038/nrmicro754 · 23.32 Impact Factor
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ABSTRACT: The notion that mimicry between a self and a microbial peptide antigen can trigger or aggravate autoimmune pathology remains a popular hypothesis in autoimmunity research. Tremendous recent progress in our understanding of the interface between the T cell receptor (TCR) and peptide/MHC complexes has revealed a vast potential for degenerate recognition of numerous structurally similar pMHC complexes by each T lymphocyte. Moreover, functional and structural studies have confirmed that structural similarity between unrelated pMHC complexes is frequently sufficient for recognition by a single TCR. However, despite clear evidence that vaccination with mimetic microbial antigens has the potential to activate autoreactive T cells, crucial evidence for triggering of autoimmunity by mimetic sequences in natural pathogens is wanting. Antigen spreading, i.e. the fact that the number of self antigens targeted by a chronic autoimmune response tends to increase with its duration, does not facilitate the task of proving initial triggering, or subsequent acceleration, of autoimmune conditions by mimetic microbial antigens. Moreover, considering that activation rather than presence of autoreactive T cells is the hallmark of autoimmune disease, the creation of an environment resulting in failure of tolerance and regulatory mechanisms, rather than emergence of novel microbial antigenic determinants, may well be at the root of autoimmunity. Based on these considerations, we contend that the mimicry concept remains largely hypothetical, and that novel carefully designed animal models are needed to make a convincing case for a role of mimicry in autoimmune diseases.Molecular Immunology 03/2004; 40(14-15):1095-102. DOI:10.1016/j.molimm.2003.11.011 · 3.00 Impact Factor
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ABSTRACT: MHC tetramers have become essential tools for the analysis of antigen specific responses of CD8+ and CD4+ T cells. However, the use of MHC class II tetramers is hampered by the relatively low yields of most current expression systems. We have devised an insect cell/baculovirus expression system in which yields of 50-70 mg of recombinant HLA-DR4 molecules, with or without covalently linked peptide, per liter of insect cell supernatant, are routinely obtained. These yields are rendered possible by an optimized design and use of DRalpha and DRbeta expression cassettes and by co-expression of a housekeeping chaperone of the endoplasmic reticulum, calreticulin, which, due to its co-secretion, increases secretion of HLA-DR molecules two- to threefold. A tetramer produced in the system specifically was shown to stain an HLA-DR4 restricted T cell line obtained from a healthy donor by in vitro priming, but which recognizes a type I diabetes autoantigen. Co-expression of chaperones may represent a general strategy for enhancing yields of recombinant proteins expressed in insect cells and facilitate production of MHC class II tetramers in the future.Journal of Immunological Methods 03/2004; 285(2):253-64. DOI:10.1016/j.jim.2003.11.011 · 2.01 Impact Factor