EFFECT OF PSEUDOMONAS-AERUGINOSA EXOTOXIN-A ON CD3-INDUCED HUMAN T-CELL ACTIVATION

The effect of Pseudomonas aeruginosa (PA) exotoxin A (P-ExA) on CD3-in duced T-cell activation was studied on the level of T-cells (prolifera tion, synthesis of interleukin (IL)-2, expression of IL-2R complex, IC AM-1,2 and LFA-1 molecules), and on the level of monocytes (expression of ICAM-1,2, LFA-1 molecules, as well as FcRI and CD14 receptors). We found that: (1) P-ExA blocked T-cell proliferation and this effect wa s totally reversed by intact monocytes, and partially by IL-2 or TPA b ut not by costimulatory cytokines (IL-1 alpha, IL-1 beta, TNF-alpha or IL-6); (2) P-ExA transiently, in short-term cultures (48 h), inhibite d synthesis of IL-2; (3) prolonged stimulation (96 h) of peripheral bl ood mononuclear cells (PBMC) or CD4+ T-cells with P-ExA in high or low doses (100 and 10 ng/ml, respectively), enhanced the level of IL-2 in the cultures; (4) P-ExA at low dose, combined with IL-1 beta, TNF-alp ha or IL-6, up-regulated synthesis of IL-2; and (5) stimulation of T-c ells with anti-CD3 monoclonal antibody (mAb) and P-ExA at high dose di minished the expression of the p55 chain but not of the p75 chain of I L-2R complex and slightly affected the expression of CD3 complex, ICAM -1,2 and LFA-1 molecules. Hence, P-ExA can regulate the level of IL-2 in cultures of CD3-induced T-cells either by inhibition of IL-2 consum ption (when P-ExA is applied in high dose), or by induction of IL-2 pr oduction (a costimulatory effect exerted by P-ExA in low dose in combi nation with monokines). Action of P-ExA on monocytes resulted in: (I) inhibition of the expression of ICAM-1,2 molecules and their ligand LF A-1 molecule; (2) low expression of FcRI receptor (a ligand for Fc par t of CD3 mAb); and (3) inhibition (over 90%) of the expression of CD14 molecule. In conclusion, P-ExA-induced anergy of T-cells depends on: (a) decrease in the affinity of IL-2R complex on activated T-cells; an d (b) inhibition of the accessory activities of monocytes. (C) 1998 El sevier Science B.V. All rights reserved.