Self versus non-self discrimination is a central theme in biology from plants to vertebrates, and is particularly relevant for lymphocytes that express receptors capable of recognizing self-tissues and foreign invaders. Comprising the third largest lymphocyte population, natural killer (NK) cells recognize and kill cellular targets and produce pro-inflammatory cytokines. These potentially self-destructive effector functions can be controlled by inhibitory receptors for the polymorphic major histocompatibility complex (MHC) class I molecules that are ubiquitously expressed on target cells. However, inhibitory receptors are not uniformly expressed on NK cells, and are germline-encoded by a set of polymorphic genes that segregate independently from MHC genes. Therefore, how NK-cell self-tolerance arises in vivo is poorly understood. Here we demonstrate that NK cells acquire functional competence through 'licensing' by self-MHC molecules. Licensing involves a positive role for MHC-specific inhibitory receptors and requires the cytoplasmic inhibitory motif originally identified in effector responses. This process results in two types of self-tolerant NK cells--licensed or unlicensed--and may provide new insights for exploiting NK cells in immunotherapy. This self-tolerance mechanism may be more broadly applicable within the vertebrate immune system because related germline-encoded inhibitory receptors are widely expressed on other immune cells.

It is widely believed that self-tolerance of natural killer (NK) cells occurs because each NK cell expresses at least one inhibitory receptor specific for a host major histocompatibility complex (MHC) class I molecule. Here we report that some NK cells lack all known self-MHC-specific inhibitory receptors, yet are nevertheless self-tolerant. These NK cells exhibit a normal cell surface phenotype and some functional activity. However, they respond poorly to class I-deficient normal cells, tumor cells, or cross-linking of stimulatory receptors, suggesting that self-tolerance is established by dampening stimulatory signaling. Thus, self- IntroductionNatural killer (NK) cells attack transformed, infected, and allogeneic cells. Target cell recognition depends on stimulatory receptors with various specificities and inhibitory receptors specific for major histocompatibility complex (MHC) class I molecules. [1][2][3] The stimulatory receptors associate with signaling adapter molecules including DNAX activating protein 12 (DAP12), CD3, or Fc receptor ␥ (FcR␥), which contain immunoreceptor tyrosine-based activation motifs (ITAMs), whereas the inhibitory receptors contain cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs). The balance of stimulatory and inhibitory signaling determines whether target cells are lysed and stimulate cytokine production.NK stimulatory receptors 3 recognize pathogen-encoded molecules (eg, Ly49H ligand 4,5 ) or host molecules that are up-regulated in transformed or infected cells (eg, NKG2D ligands 6 ). Because NK cells attack certain uninfected and untransformed cell types, such as bone marrow cells or lymphoblasts from MHC-deficient or allogeneic animals, it is believed that even these normal cells express a ligand that is recognized by an NK stimulatory receptor (reviewed in Raulet et al 7 ).There are 3 different families of MHC-specific inhibitory receptors that have been defined: Ly49, a family of approximately 10 lectinlike receptors expressed by murine NK cells 8 ; killer immunoglobulin (Ig)-like receptors (KIRs), a family of approximately 10 Ig-like receptors expressed by human NK cells 2,9 ; and CD94/NKG2A, a lectinlike receptor heterodimer expressed by both human and murine NK cells. 10,11 Ly49 receptors and KIRs bind to classical class Ia MHC molecules. In contrast, CD94/ NKG2A interacts with a nonclassical class Ib molecule called Qa-1 in mice and HLA-E in humans. The Qa-1/HLA-E molecules are ␤2-microglobulin (␤2m)-dependent and present a conserved peptide from the cleaved signal sequences of certain class Ia MHC molecules, which is recognized by CD94/NKG2A. Therefore, the CD94/NKG2A receptor indirectly recognizes class Ia molecules. All 3 types of inhibitory NK receptors distinguish subgroups of MHC class I molecules and all are expressed in a variegated fashion such that each NK cell expresses a more or less random set of receptors, with an average number per cell of 2 to 3. 12,13 Whether a target cell inhibits a given NK cell depends on whether the NK cell express...

Experimental infection with mouse cytomegalovirus (MCMV) has been used to elucidate the intricate host-pathogen mechanisms that determine innate resistance to infection. Linkage analyses in F(2) progeny from MCMV-resistant MA/My (H2 (k)) and MCMV-susceptible BALB/c (H2 (d)) and BALB.K (H2 (k)) mouse strains indicated that only the combination of alleles encoded by a gene in the Klra (also called Ly49) cluster on chromosome 6, and one in the major histocompatibility complex (H2) on chromosome 17, is associated with virus resistance. We found that natural killer cell-activating receptor Ly49P specifically recognized MCMV-infected cells, dependent on the presence of the H2 (k) haplotype. This binding was blocked using antibodies to H-2D(k) but not antibodies to H-2K(k). These results are suggestive of a new natural killer cell mechanism implicated in MCMV resistance, which depends on the functional interaction of the Ly49P receptor and the major histocompatibility complex class I molecule H-2D(k) on MCMV-infected cells.

The present study examined the association between child sexual abuse (CSA) and a range of positive and negative aspects of women's sexual well-being. We also investigated the extent to which women's cognitive-affective sexual appraisals mediated these relationships. Participants were 272 female community college and university students. CSA involving fondling only was generally not associated with adverse sexual outcomes. However, the women who had experienced CSA involving sexual penetration or attempted sexual penetration were (a) more likely to be sexually revictimized in adulthood; (b) more likely to have engaged in casual sex, unprotected sex, and voluntary sexual abstinence; and (c) reported fewer sexual rewards, more sexual costs, and lower sexual self-esteem. These findings held over and above the effects of nonsexual abuse in childhood, and as predicted, sexual self-esteem partially or fully mediated most of these relationships. Nonsexual abuse in childhood and adult sexual victimization were also uniquely associated with a number of adverse sexual outcomes. However, outcomes were not worse for women who had experienced CSA involving actual or attempted sexual penetration and sexual assault in adulthood. The results highlight the fact that CSA is a serious and widespread problem with significant implications for adult women's sexual functioning.Suzanne R. Lemieux, Forensic Assessment and Outpatient Services, Calgary Health Region;