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Altered Selection of CD4⁺ T Cells by Class II MHC Bound with Dominant and Low Abundance Self-Peptides¹

Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912

We have investigated the development of CD4⁺ T cells in mice expressing low levels of transgenic class II MHC molecules (A^b) preoccupied with covalent peptide (Ep), which in the presence of invariant chain (Ii) is extensively cleaved and replaced with self-derived peptides. In these mice, the transgenic A^b molecules, bound with predominant peptide (Ep) and with multiple self-peptides, selected more CD4⁺ T cells than A^b/self-peptide complexes expressed in wild-type mice. The enhanced outcome of thymic selection was a result of impaired negative selection, rather than more efficient positive selection by an overall lowered abundance of self-derived A^b/peptide complexes. Peripheral CD4⁺ T cells in the A^bEpIi⁺ mice had memory phenotype, often followed by polyclonal activation of B cells. The A^bEpIi⁺ mice preserved their good health and had a normal life span despite the profound number of activated CD4⁺ T cells and B cells in peripheral lymphoid organs, moderate hypergammaglobulinemia, and deposited complexes in the kidneys. We propose that CD4⁺ T cells positively selected due to low avidity for high abundant A^bEp complex avoid negative selection on A^b molecules loaded with low abundant peptides and become self-reactive in the peripheral lymphoid organs.

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