LYTIC SUSCEPTIBILITY OF TARGET-CELLS TO CYTOTOXIC T-CELLS IS DETERMINED BY THEIR CONSTITUTIVE MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I ANTIGEN EXPRESSION AND CYTOKINE-INDUCED ACTIVATION STATUS

Cytotoxic T-cell lines (TCL) were raised in vitro using stimulator cel ls with a defined major histocompatibility complex (MHC) mismatch and tested in a cytotoxic chromium-release assay against haemopoietic and non-haemopoietic target cells from the original stimulator. Monoclonal antibody (mAb)-blocking experiments and simultaneous determination of MHC class I, class II, lymphocyte function-associated antigen-1 (LFA- 1) and intracellular adhesion molecule-1 (ICAM-1) density by quantitat ive radioimmunometric methods and flow cytometry on target cells demon strated that lysis was restricted by MHC class I and dependent upon th e constitutive MHC class I antigen expression. Measurements showed a h igh constitutive expression of class I MHC antigens on peripheral bloo d mononuclear cells (PBMC), but a low one on keratinocytes (K). Also, PBMC were more susceptible to lysis by TCL than K. Interferon-gamma (I FN-gamma) treatment of K resulted in increased MHC class I antigen exp ression and enhanced lytic susceptibility to TCL. IFN-alpha and tumour necrosis factor-alpha (TNF-alpha) treatment, which did not modulate M HC class I antigen expression on K, did not influence the amount of K lysis either. None of the cytokines tested in this analysis, however, increased the expression of MHC class I, class II, ICAM-1 and LFA-1 on PBMC. Only IFN-gamma pretreatment showed a minimal, statistically sig nificant increase in MHC class I antigen expression. In spite of the m inimal effect of IFN-gamma and no effect of IFN-alpha on class I MHC e xpression, pretreatment of target cells with both cytokines considerab ly increased their lytic susceptibility. The mechanism of cytokine-ind uced enhanced lytic susceptibility to TCL was not explained by increas ed MHC class I, LFA-1 or ICAM-1 expression, since no correlation was f ound between surface expression of these molecules and lytic susceptib ility to TCL. These data demonstrate that: (1) the constitutive densit y of MHC class I antigens determines the extent of TCL lysis; (2) IFN- gamma, and not IFN-alpha or TNF-alpha, controls the amount of K target cell lysis by increasing their MHC class I antigen expression; and (3 ) IFN-gamma and IFN-alpha control the amount of PBMC target cell lysis by a mechanism independent of MHC class I, ICAM-1 or LFA-1 expression .