Post-thymic selection of peripheral CD4(+) T-lymphocytes on class II majorhistocompatibility antigen-bearing cells

Following positive and negative selection in the thymus, mature CD4(+) T-ce lls emigrate into peripheral lymphoid organs. Whether resting T-cells requi re periodic stimulation to remain viable in the absence of antigen is impor tant for understanding peripheral T-cell homeostasis. A prerequisite for T- cell receptor (TCR)-mediated signals in maintaining peripheral CD4(+) T-cel l longevity has been demonstrated. Here, we show in mice expressing a mutan t I-A(beta) transgene on an I-A(beta) knockout backgound that naive CD4(+) T-cells also require engagement of their CD4 coreceptors by peripheral, cla ss II MHC-bearing cells for their survival. The transgene's product combine s with endogenous A(alpha), but this mutant A(alpha)A(beta) heterodimer can not interact with CD4 molecules, although it efficiently presents antigens to TCRs. Resting CD4(+) T-lymphocytes from mutant A(beta) transgenic mice d ie by apoptosis at a much higher rate than do CD4(+) T-cells from normal mi ce. Apoptosis of CD4(+) T-cells in mutant A(beta) transgenic mice is partia lly mediated by Fas. Adoptive transfer experiments revealed that the increa se in apoptosis is due to a lack of interactions with mutant MHC class II r ather than to an intrinsic defect in the CD4(+) T-cells selected on mutant A(beta)-expressing thymic epithelial cells. Thus, interactions between CD4 and MHC class II molecules contribute to the regulation of homeostasis in t he peripheral immune system. Our results further suggest that thymic emigra nt cells are continuously retested in the periphery for appropriate corecep tor interactions. Peripheral selection may be important in eliminating pote ntially autoreactive T-cells.