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Ennio Carbone^*,, Giuseppina Ruggiero^*, Giuseppe Terrazzano^*, Carmen Palomba^*, Ciro Manzo, Silvia Fontana, Hergen Spits^||, Klas Kärre^¶, and Serafino Zappacosta^*

From the ^* Cattedra di Immunologia, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Naples, Italy; Oncologia Sperimentale C, Immunologia, Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy; Centro di Endocrinologia ed Oncologia Sperimentale del CNR, Naples, Italy; ^|| Division of Immunology, The Netherlands Cancer Institute, Amsterdam, Holland; and ^¶ Microbiology and Tumorbiology Center, Karolinska Institutet, Stockholm, Sweden

NK recognition is regulated by a delicate balance between positive signals initiating their effector functions, and inhibitory signals preventing them from proceeding to cytolysis. Knowledge of the molecules responsible for positive signaling in NK cells is currently limited. We demonstrate that IL-2–activated human NK cells can express CD40 ligand (CD40L) and that recognition of CD40 on target cells can provide an activation pathway for such human NK cells. CD40-transfected P815 cells were killed by NK cell lines expressing CD40L, clones and PBLderived NK cells cultured for 18 h in the presence of IL-2, but not by CD40L-negative fresh NK cells. Cross-linking of CD40L on IL-2–activated NK cells induced redirected cytolysis of CD40-negative but Fc receptor-expressing P815 cells. The sensitivity of human TAP-deficient T2 cells could be blocked by anti-CD40 antibodies as well as by reconstitution of TAP/MHC class I expression, indicating that the CD40-dependent pathway for NK activation can be downregulated, at least in part, by MHC class I molecules on the target cells. NK cell recognition of CD40 may be important in immunoregulation as well as in immune responses against B cell malignancies.

¹ Abbreviations used in this paper: CD40L, CD40 ligand; KIR, killer cell inhibitory receptors; o.n., overnight.

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