Epitope-Dependent Inhibition of T Cell Activation by theEaTransgene: An Explanation for Transgene-Mediated Protection from Murine Lupus

Abstract

A high level expression of the Ead transgene encoding the I-E α-chain is highly effective in the suppression of lupus autoantibody production in mice. To explore the possible modulation of the Ag-presenting capacity of B cells as a result of the transgene expression, we assessed the ability of the transgenic B cells to activate Ag-specific T cells in vitro. By using four different model Ag-MHC class II combinations, this analysis revealed that a high transgene expression in B cells markedly inhibits the activation of T cells in an epitope-dependent manner, without modulation of the I-E expression. The transgene-mediated suppression of T cell responses is likely to be related to the relative affinity of peptides derived from transgenic I-E α-chains (Eα peptides) vs antigenic peptides to individual class II molecules. Our results support a model of autoimmunity prevention based on competition for Ag presentation, in which the generation of large amounts of Eα peptides with high affinity to I-A molecules decreases the use of I-A for presentation of pathogenic self-peptides by B cells, thereby preventing excessive activation of autoreactive T and B cells.

Differential Role of Three Major New Zealand Black-Derived Loci Linked with Yaa-Induced Murine Lupus Nephritis

“…It has been previously shown that the introduction of two copies of the functional Ea transgene in lupus-prone BXSB mice (H2 b ) is sufficient to prevent the development of SLE (42). Although the precise mechanism of the protection of SLE by I-E has not fully been elucidated, our recent results support the hypothesis that formation of I-E ␣-chain-derived peptides, which display a high affinity to I-A molecules, in B cells may decrease the use of I-A molecules for the presentation of pathogenic self peptides, thereby limiting the activation of autoreactive T and B cells (43).…”

The MHC Haplotype H2b Converts Two Pure Nonlupus Mouse Strains to Producers of Antinuclear Antibodies

“…This hypothesis, like that advanced by Iwamoto et al to explain the protective effect of transgene-encoded E␣ chains in BXSB and related lupus mice (see Introduction) (20), assumes that the anti-chromatin Ab responses depend on Th cells and autoantigen presentation on I-A b . In this context, it has been proposed that genetic defects of lupus-prone mice lower TCR activation thresholds for autoantigen (20) (54,55). However, the normal genetic backgrounds of BALB.B and C3.SW mice suggest that this putative mechanism does not apply to these mice.…”

H2E-Derived Eα52-68 Peptide Presented by H2Ab Interferes with Clonal Deletion of Autoreactive T Cells in Autoimmune Thyroiditis

“…Of particular note is the finding that H2A b class II molecules can bind a peptide derived from the conserved E␣-chain (E␣52-68) with high affinity (13). In transgenic or recombinant mice expressing both H2A b and H2E b class II molecules, 10 -40% of the H2A b molecules harbor E␣52-68 in the peptide-binding cleft (E␣52-68/A b ) (13,14). Moreover, altering the composition of H2A b -binding peptides by expression of E␣ has been shown to affect the presentation of immunogenic epitopes and thus reduce T cell activation (14,15).…”

“…In transgenic or recombinant mice expressing both H2A b and H2E b class II molecules, 10 -40% of the H2A b molecules harbor E␣52-68 in the peptide-binding cleft (E␣52-68/A b ) (13,14). Moreover, altering the composition of H2A b -binding peptides by expression of E␣ has been shown to affect the presentation of immunogenic epitopes and thus reduce T cell activation (14,15). One of us has demonstrated that a peptide derived from HLA-DR, the human H2E equivalent, and presented by HLA-DQ, the human H2A equivalent, lowered susceptibility to collagen-induced arthritis (CIA) (16 b .…”

“…Moreover, when the Ea gene is expressed in an H2 b strain, anywhere from 10 to 40% of all A b molecules on APC are occupied by this self peptide (13,14). We used the mAb Y-Ae, which specifically labels the E␣52-68/A b complex, to verify that APC from our A ϩ E ϩ strain, but not from the A ϩ E Ϫ strain, contains E␣52-68 (Fig.…”