Autoreactivity of T cells from nonobese diabetic mice: An I-A^g7-dependent reaction

Abstract

Mice bearing the I-A g7 class II major histocompatibility complex molecules contain a high number of spontaneous autoreactive T cells, as estimated by limitingdilution assays. We found this autoreactivity in various strains that bear the I-A g7 molecule, such as the nonobese diabetic (NOD) mouse strain, which spontaneously develops autoimmune diabetes. However, NOD mice strains that do not express the I-A g7 molecule, but instead express I-A b , do not have a high incidence of autoreactive T cells. About 15% of the autoreactive T cells also recognize the I-A g7 molecule expressed in the T2 line, which is defective in the processing of protein antigens. We interpret this to mean that some of the T cells may interact with class II molecules that are either devoid of peptides or contain a limited peptide content. We also find a high component of autoreactivity among antigenspecific T cell clones. These T cell clones proliferate specifically to protein antigens but also have a high level of reactivity to antigen-presenting cells not pulsed with antigen. Thus, the library of T cell receptors in NOD mice is skewed to autoreactivity, which we speculate is based on the weak peptidebinding properties of I-A g7 molecules.

Do the peptide-binding properties of diabetogenic class II molecules explain autoreactivity?

“…The 9-mer binding core is shown in bold and underlined. In other results, the Glu124 was identified as the P9-MHC anchor residue a Adapted from the published study of Kanagawa et al [29] Curr Opin Immunol. Author manuscript; available in PMC 2009 February 1.…”

“…Earlier studies by Kanagawa et al and Ridgway et al noted that the expression of I-A g7 alone, independent of the genetic background, was sufficient for escape of autoreactive T cells -i.e. these were CD4+ T cells that reacted with syngeneic APCs alone with no need for any exogenous antigens [29][30][31]. Note in Table 2 from the experiments of Kanagawa et al [29], the frequencies of autoreactive T cells was significantly higher in I-A g7 -expressing strains and independent of the NOD background genes.…”

Molecular Basis for Recognition of an Arthritic Peptide and a Foreign Epitope on Distinct MHC Molecules by a Single TCR

“…The I-A g7 ␣␤ heterodimer has both a shortened cell surface half life and a poor ability to retain bound peptides (28). These traits have been correlated in vivo with an elevated frequency of autoreactive T cells, which is proposed to originate from less efficient negative selection on this MHC allele (29,30). Ineffective negative selection of autoreactive T cells is also a proposed mechanism by which RA-associated MHC alleles confer disease susceptibility (31).…”

Reduced Regulatory T Cell Diversity in NOD Mice Is Linked to Early Events in the Thymus

“…T cells play an essential role in disease pathogenesis and, through the activity of Tregs, in the control of disease progression. A number of reports have described functional abnormalities in NOD Tregs attributed to mechanisms including agerelated decline of active, membrane-bound TGF-b (4), IL-2 insufficiency (5), defective Ag presentation (6), and resistance of conventional CD4 T cells to regulation (7). NOD Treg cellularity has also been reported to be low (8), although subsequent analysis failed to confirm this observation (9).…”