MHC CLASS-I MOLECULES ARE IMPLICATED IN COSTIMULATORY SIGNALS DURING TCR CD3-INDUCED ACTIVATION/

Mouse MHC class I-specific mAbs recognizing the alpha 1/alpha 2, but n ot those directed against the alpha 3 domain of the molecule, inhibite d RNA, protein, and DNA synthesis of splenic T cells in response to st imulation through the TCR/CD3 complex. Similar inhibition was seen wit h LFA-1-specific mAbs under the same stimulation conditions. The effec t of class I- and LPA-1-specific mAbs reflected a decrease of both IL- 2 and IFN-gamma synthesis and IL-2 receptor alpha chain induction. IL- 2, IL-2 receptor alpha chain, IFN-gamma, c-fos, c-jun, and c-myc mRNAs were not detected. Activation of AP-1 (c-Fos and c-Jun proteins) and NF-kappa B transcription factors were also inhibited. Inhibition was o bserved both after treatment of cells in culture and after intravenous injection of Abs in mice. Although bulk phosphorylation was inhibited , early tyrosine phosphorylation and calcium ion influx were normally induced. Protein phosphatase inhibitors did not reverse this inhibitio n, ruling out an enhanced activation of these enzymes in the observed inhibition. Cell surface expression of one of early PKC activation mar ker, CD69 was also inhibited. Phorbol esters that directly activate PK C prevented inhibition. Thus, class I molecules are implicated in sign al transduction involved at an early stage for T cell activation in a manner that suggests their implication in accessory signal transmissio n that contributes to the regulation of PKC activity. (C) 1996 Academi c Press, Inc.