CD161 (NKR-P1A) COSTIMULATION OF CD1D-DEPENDENT ACTIVATION OF HUMAN T-CELLS EXPRESSING INVARIANT V-ALPHA-24J-ALPHA-Q T-CELL RECEPTOR-ALPHA CHAINS

A population of human T cells expressing an invariant V alpha 24J alph a Q T cell antigen receptor (TCR) alpha chain and high levels of CD161 (NKR-P1A) appears to play an immunoregulatory role through production of both T helper (Th) type 1 and Th2 cytokines. Unlike other CD161(+) T cells, the major histocompatibility complex-like nonpolymorphic CD1 d molecule is the target for the TCR expressed by these T cells (V alp ha 24(invt) T cells) and by the homologous murine NK1 (NKR-P1C)(+) T c ell population. In this report, CD161 was shown to act as a specific c ostimulatory molecule for TCR-mediated proliferation and cytokine secr etion by V alpha 24(invt) T cells. However, in contrast to results in the mouse, ligation of CD161 in the absence of TCR stimulation did not result in V alpha 24(invt) T cell activation, and costimulation throu gh CD161 did not cause polarization of the cytokine secretion pattern. CD161 monoclonal antibodies specifically inhibited V alpha 24(invt) T cell proliferation and cytokine secretion in response to CD1d(+) targ et cells, demonstrating a physiological accessory molecule function fo r CD161. However, CD1d-restricted target cell lysis by activated V alp ha 24(invt) T cells, which involved a granule-mediated exocytotic mech anism, was CD161-independent. In further contrast to the mouse, the si gnaling pathway involved in V alpha 24(invt) T cell costimulation thro ugh CD161 did not appear to involve stable association with tyrosine k inase p56(Lck). These results demonstrate a role for CD161 as a novel costimulatory molecule for TCR-mediated recognition of CD1d by human V alpha 24(invt) T cells.