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CD161 (NKR-P1A) Costimulation of CD1d-dependent Activation of Human T Cells Expressing Invariant V24JQ T Cell Receptor Chains

Mark Exley^*,, Steven Porcelli^,, Margo Furman^*,, Jorge Garcia^*,, and Steven Balk^*,

From the ^* Department of Cancer Biology, Hematology/Oncology, Beth Israel-Deaconess Medical Center, Boston, Massachusetts 02215; the Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts 02215; and the Harvard Medical School, Boston, Massachusetts 02115

A population of human T cells expressing an invariant V24JQ T cell antigen receptor (TCR) 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 CD1d molecule is the target for the TCR expressed by these T cells (V24^invt T cells) and by the homologous murine NK1 (NKR-P1C)⁺ T cell population. In this report, CD161 was shown to act as a specific costimulatory molecule for TCR-mediated proliferation and cytokine secretion by V24^invt T cells. However, in contrast to results in the mouse, ligation of CD161 in the absence of TCR stimulation did not result in V24^invt T cell activation, and costimulation through CD161 did not cause polarization of the cytokine secretion pattern. CD161 monoclonal antibodies specifically inhibited V24^invt T cell proliferation and cytokine secretion in response to CD1d⁺ target cells, demonstrating a physiological accessory molecule function for CD161. However, CD1d-restricted target cell lysis by activated V24^invt T cells, which involved a granule-mediated exocytotic mechanism, was CD161-independent. In further contrast to the mouse, the signaling pathway involved in V24^invt T cell costimulation through CD161 did not appear to involve stable association with tyrosine kinase p56^Lck. These results demonstrate a role for CD161 as a novel costimulatory molecule for TCR-mediated recognition of CD1d by human V24^invt T cells.

Key Words: CD1d • CD161 • costimulation • V24JQ • T cells

For antibody and/or cell reagents, we wish to thank Drs. A. Bendelac, J. Hansen, R. Kurrle, L. Lanier, A. Lanzavecchia, M. Lopez-Botet, D. Olive, A. Poggi, E. Reinherz, M. Robertson, and J. Ritz. We would also like to thank Drs. S.B. Wilson, S. Kent, R. Blumberg, and our colleagues in the Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, especially J. Gumperz and D.B. Moody, for unpublished results, advice, or comments on the manuscript.

Abbreviations used: CHO, Chinese hamster ovary; DN, CD4/ CD8 double negative; V24^invt, V24JQ TCR-expressing.

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