Primary hormonogenic sites as conserved autoepitopes on thyroglobulin in murine autoimmune thyroiditis: role of MHC class II.
A few synthetic peptides corresponding to amino acid sequences on human thyroglobulin (Tg) have been reported to induce moderate thyroiditis or activate mouse Tg (MTg)-primed T cells to transfer thyroiditis in mice susceptible to experimental autoimmune thyroiditis. Using three pairs of 12-mer peptides (1-12, 2549-2560, 2559-2570), with thyroxine (T4) or noniodinated thyronine (T0) at the conserved, hormonogenic site 5, 2553, or 2567 respectively, we reported that iodination was not required for a Tg hormonogenic site to be a thyroiditogenic autoepitope. To determine the relative importance of MHC class II and T cell receptor (TCR) repertoire, we compared two EAT-susceptible k and s (CBA and A.SW) haplotypes and their respective MHC-identical strain (C57BR and SJL) with approximately 50% genomic deletion of TCR Vbeta genes. Whereas k and s strains develop MTg-induced EAT, vigorous immunization with peptides containing T4 or T0 at either 5 or 2553, but not at 2567, led to mild (10-20%) thyroiditis only in some mice of either k strain. TCR Vbeta gene differences played a minor role. T cell responses to all peptide pairs were quite similar in CBA and C57BR mice, and both hT0(2553) and hT4(2553) reciprocally primed and stimulated their T cells. In adoptive transfer, SJL mice were somewhat more responsive to peptide activation than A.SW but much weaker than k strains. By comparing T4- and T0-containing peptides in different haplotypes, we show further that antigenicity of conserved hormonogenic sites is intrinsic, dependent more on amino acid sequence and binding to appropriate class II molecules and less on TCR repertoire or iodination of T0.
Wan
Q
Q
St. John Hospital and Medical Center, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Motte
R W
RW
McCormick
D J
DJ
Fuller
B E
BE
Giraldo
A A
AA
David
C S
CS
Kong
Y M
YM
D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D004195:Disease Models, Animal; D000939:Epitopes / Q000032:analysis; D005260:Female; D005802:Genes, MHC Class II / Q000502:physiology; D008213:Lymphocyte Activation; D051379:Mice; D008805:Mice, Inbred A; D008808:Mice, Inbred CBA; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology; D013954:Thyroglobulin / Q000276:immunology*; D013967:Thyroiditis, Autoimmune / Q000276:immunology*; D013970:Thyronines / Q000276:immunology*; D013974:Thyroxine / Q000276:immunology*
D000939:Epitopes; D016693:Receptors, Antigen, T-Cell, alpha-beta; D013970:Thyronines; D013954:Thyroglobulin; D013974:Thyroxine