Low‐avidity recognition by CD4+ T cells directed to self‐antigens

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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.