The murine nonclassical class I major histocompatibility complex-like CD1.1 molecule protects target cells from lymphokine-activated killer cell cytolysis

Classical class I major histocompatibility complex (MHC) molecules, as well as the nonclassical class I histocompatibility leukocyte antigen (HLA)-E m olecule, can negatively regulate natural killer (NK) cell cytotoxicity thro ugh engagement of NK Inhibitory receptors. We show that expression of murin e (m)CD1.1, a nonpolymorphic nonclassical MHC class I-like molecule encoded outside the MHC, protects NK-sensitive RMA/S target cells from adherent ly mphokine-activated killer cell (A-LAIC) cytotoxicity. Passage of effector c ells in recombinant interleukin (rIL)-2 enhanced protection by mCD1.1, sugg esting an expansion of relevant A-LAK population(s) or modulation of A-LAK receptor expression. Murine CD1.1 conferred protection from lysis by rIL-2- activated spleen cells of recombination activating gene (Rag)-1(-/-) mice, which lack B and T cells, demonstrating that mCD1.1 can protect RMA/S cells from lysis by NK cells. An antibody specific for mCD1.1 partially restored A-LAK lysis of RMA/S.CD1.1 transfectants, indicating that cell surface mCD 1.1 can confer protection from lysis; therefore, mCD1.1 possibly acts throu gh interaction with an NK inhibitory receptor. CD1.1 is by far the most div ergent class I molecule capable of regulating NK cell activity. Finally, mC D1.1 expression rendered RMA/S cells resistant to lysis by A-LAK of multipl e mouse strains. The conserved structure of mCD1.1 and pattern of mCD1.1 re sistance from A-LAK lysis suggest that mCD1.1 may be a ligand for a conserv ed NK inhibitory receptor.