Altered selection of CD4(+) T cells by class II MHC bound with dominant and low abundance self-peptides

We have investigated the development of CD4(+) T cells in mice expressing l ow levels of transgenic class II MHC molecules (Ab) preoccupied with covale nt peptide (Ep), which in the presence of invariant chain (Zi) is extensive ly cleaved and replaced with self-derived peptides. In these mice, the tran sgenic A(b) molecules, bound with predominant peptide (Ep) and with multipl e self-peptides, selected more CD4(+) T cells than A(b)/self-peptide comple xes expressed in wild-type mice. The enhanced outcome of thymic selection w as a result of impaired negative selection, rather than more efficient posi tive selection by an overall lowered abundance of self-derived A(b)/peptide complexes. Peripheral CD4(+) T cells in the A(b)EpIi(+) mice had memory ph enotype, often followed by polyclonal activation of B cells. The A(b)EpIi() mice preserved their good health and had a normal life span despite the p rofound number of activated CD4(+) T cells and B cells in peripheral lympho id organs, moderate hypergammaglobulinemia, and deposited complexes in the kidneys. We propose that CD4(+) T cells positively selected due to low avid ity for high abundant A(b)Ep complex avoid negative selection on A(b) molec ules loaded with low abundant peptides and become self-reactive in the peri pheral lymphoid organs.