MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I MOLECULES MODULATE ACTIVATION THRESHOLD AND EARLY SIGNALING OF T-CELL ANTIGEN RECEPTOR GAMMA DELTASTIMULATED BY NONPEPTIDIC LIGANDS/

Killer cell inhibitory receptors and CD94-NKG2-A/B heterodimers are ma jor histocompatibility complex class I-specific inhibitory receptors e xpressed by natural killer cells, T cell antigen receptor (TCR)-gamma/ delta cells, and a subset of TCR-alpha/beta cells. Wie studied the fun ctional interaction between TCR-gamma/delta and CD94, this inhibitory receptor being expressed on the majority of gamma/delta T cells. When engaged by human histocompatibility leukocyte antigen class I molecule s, CD94 downmodulates activation of human TCR-gamma/delta by phosphory lated ligands. CD94-mediated inhibition is more effective at low than at high doses of TCR ligand, which may focus T cell responses towards antigen-presenting cells presenting high amounts of antigen. CD94 enga gement has major effects on TCR signaling cascade. It facilitates recr uitment of SHP-1 phosphatase to TCR-CD3 complex and affects phosphoryl ation of Lck and ZAP-70 kinase, but not of CD3 zeta chain upon TCR tri ggering. These events may cause abortion of proximal TCR-mediated sign aling and set a higher TCR activation threshold.