Post-thymic selection of peripheral CD4+ T-lymphocytes on class II major histocompatibility antigen-bearing cells

Following positive and negative selection in the thymus, mature CD4(+) T-cells emigrate into peripheral lymphoid organs. Whether resting T-cells require periodic stimulation to remain viable in the absence of antigen is important for understanding peripheral T-cell homeostasis. A prerequisite for T-cell receptor (TCR)-mediated signals in maintaining peripheral CD4(+) T-cell longevity has been demonstrated. Here, we show in mice expressing a mutant 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, class II MHC-bearing cells for their survival. The transgene's product combines with endogenous A(alpha), but this mutant A(alpha)A(beta) heterodimer cannot interact with CD4 molecules, although it efficiently presents antigens to TCRs. Resting CD4(+) T-lymphocytes from mutant A(beta) transgenic mice die by apoptosis at a much higher rate than do CD4(+) T-cells from normal mice. Apoptosis of CD4(+) T-cells in mutant A(beta) transgenic mice is partially mediated by Fas. Adoptive transfer experiments revealed that the increase in apoptosis is due to a lack of interactions with mutant MHC class II rather 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 the peripheral immune system. Our results further suggest that thymic emigrant cells are continuously retested in the periphery for appropriate coreceptor interactions. Peripheral selection may be important in eliminating potentially autoreactive T-cells.