Low-avidity recognition by CD4+ T cells directed to self-antigens.
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.
Gebe
John A
JA
Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101, USA. jgebe@vmresearch.org
Falk
Ben A
BA
Rock
Kellee A
KA
Kochik
Sharon A
SA
Heninger
Anne K
AK
Reijonen
Helena
H
Kwok
William W
WW
Nepom
Gerald T
GT
D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005968:Glutamate Decarboxylase / Q000276:immunology; D015804:HLA-DR4 Antigen / Q000737:chemistry / Q000378:metabolism; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology; D006801:Humans; D006825:Hybridomas / Q000276:immunology; D007114:Immunization; D007527:Isoenzymes / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis
D001324:Autoantigens; D015804:HLA-DR4 Antigen; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007527:Isoenzymes; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2