No abstract

Metazoan organisms may discriminate between self and non-self not only by the presence of foreign antigens but also by the absence of normal self markers. Mammalian adaptive immune responses use the first strategy, with the additional requirement that foreign antigens are recognized in the context of self-major histocompatibility complex (MHC) products at the cell surface. Aberrant cells which fail to express MHC products adequately can therefore avoid detection. A more primitive but complementary defence system, eliminating such cells on the basis of absent self-markers, is suggested by a re-interpretation of phenomena associated with metastasis and natural resistance. We now show that murine lymphoma cells selected for loss of H-2 expression are less malignant after low-dose inoculation in syngeneic hosts than are wild-type cells, and that the rejection of such cells is non-adaptive. On the basis of our data, we suggest that natural killer cells are effector cells in a defence system geared to detect the deleted or reduced expression of self-MHC.

Major histocompatibility complex (MHC) class I molecules present antigen by transporting peptides from intracellularly degraded proteins to the cell surface for scrutiny by cytotoxic T cells. Recent work suggests that peptide binding may be required for efficient assembly and intracellular transport of MHC class I molecules, but it is not clear whether class I molecules can ever assemble in the absence of peptide. We report here that culture of the murine lymphoma mutant cell line RMA-S at reduced temperature (19-33 degrees C) promotes assembly, and results in a high level of cell surface expression of H-2/beta 2-microglobulin complexes that do not present endogenous antigens, and are labile at 37 degrees C. They can be stabilized at 37 degrees C by exposure to specific peptides known to interact with H-2Kb or Db. Our findings suggest that, in the absence of peptides, class I molecules can assemble but are unstable at body temperature. The induction of such molecules at reduced temperature opens new ways to analyse the nature of MHC class I peptide interactions at the cell surface.

We describe a cell in which association of a major histocompatibility complex class I heavy chain with beta 2-microglobulin is induced by a peptide derived from influenza nucleoprotein. Association of antigenic peptides with the binding site of class I molecules may be required for correct folding of the heavy chain, association with beta 2-microglobulin and transport of the antigen-MHC complex to the cell surface.

Three independent variants with a profound reduction of cell surface H-2 have been selected from the C57BL/6 mouse-derived RBL-5 and EL-4 T lymphomas. After subcutaneous inoculation of low cell doses in syngeneic mice, the H-2- variants failed to grow out, whereas the H-2+ control lines showed progressive growth. No difference in growth rate or cloning efficiency was detectable in tissue culture. The in vivo difference in tumor outgrowth was analyzed in detail for one of the H-2-low lines. The outgrowth difference remained after the H-2-low variant and the control line had been injected subcutaneously in opposite flanks of the same mouse, and it was not dependent upon activity of mature T cells, since the same result was seen in athymic nude mice. The difference was partially sensitive to irradiation of the hosts. When mice were pretreated with anti-asialo GM1 antiserum, known to depress natural killer (NK) cell activity, the difference in outgrowth was abolished, and both the control line and the H-2- variant showed progressive growth in vivo. Experiments comparing the distribution and survival of isotope-prelabeled variant and wild type cells indicated that a rapid elimination of the former took place within 24 h after intravenous injection. These differences in tumor elimination were not seen in mice treated with anti-asialo GM1 antiserum. We conclude that the reduced tumorigenicity of sublines with impaired H-2 expression is largely, if not exclusively due to rapid elimination by NK cells. These findings may reflect an inverse, indirect relation between factors controlling H-2 expression and NK sensitivity. Another possible explanation is that major histocompatibility complex (MHC)-encoded gene products are directly involved in a regulatory signal in the NK cell system. According to this interpretation, immunological selectivity in the NK cell system would be achieved by the failure to recognize self-MHC, irrespective of the presence of foreign antigens, i.e. by detection of no-self rather than of nonself. This may also explain previous observations on H-2-linked hybrid resistance against lymphoid grafts and changes in H-2 phenotypes associated with tumor progression.

NK cells use a variety of receptors to detect abnormal cells, including

IntroductionNatural killer (NK) cells take part in the defense against virusinfected, neoplastic, and allogeneic cells. 1,2 NK-cell function is balanced by signals from inhibitory and activating receptors. If the balance is tipped toward activation, cytolysis and cytokine production are initiated. 3 Murine inhibitory receptors belong to the Ly49 or the NKG2/CD94 family. 4 Their ligands are MHC class I molecules, and MHC class I deficiency, or the presence of MHC class I alleles that fail to bind the inhibitory receptors, therefore results in "missing self" recognition. 5 NK cells from mice and humans without MHC class I expression are incapable of rejecting MHC class I-deficient cells, showing that they have developed hyporesponsiveness in the MHC-deficient environment. [6][7][8] Conversely, NK cells lacking inhibitory receptors for self-MHC class I are hyporesponsive despite normal MHC class I expression. [9][10][11] Studies with MHC class I transgenic mice provided evidence that individual MHC class I alleles deliver educational signals to NK cells, and this conveys novel reactivity to the NK-cell system. 12,13 Altogether, these data imply an education mechanism, in which host MHC class I molecules both secure self-tolerance and convey functional capacity to NK cells. 6,7,9,10 The question of how MHC class I alleles influence NK-cell functionality is important for the understanding of hematopoietic stem cell transplantation across killer cell Ig-like receptor (KIR)/ HLA donor-recipient mismatched barriers, in which NK cells elicit therapeutically beneficial missing self-rejections of recipient leukemic cells. 14 Epidemiologic correlations between certain KIR/HLA genotypes and disease susceptibility and outcome constitute another area in which NK-cell education is of potential importance. [15][16][17] Several models have been proposed to explain the educational effects of MHC class I molecules on NK-cell function.Kim and colleagues suggested that NK cells are initially hyporesponsive and become "licensed" when their Ly49 receptors engage self-MHC class I during maturation. 10,18 In another model, NK cells are responsive by default, and become hyporesponsive, or "disarmed," in the absence of inhibitory input. 9,19 A commonly held view in NK-cell education is that an NK cell is either educated or not, depending on whether its inhibitory receptors are engaged during NK-cell education. This view is based on the notions that Ly49 receptors discriminate sharply between MHC class I alleles 20,21 and that the functional capacity of NK-cell subsets to develop missing self-activity depend on the MHC setup. 22 Our recent studies showed, however, that individual MHC class I alleles are not equally efficient in educating NK cells for the capacity to reject MHC-deficient cells in vivo; some display a good "educating impact" on the NK-cell system, while some MHC class I alleles are less efficient. 23 Here, we provide data that explain the difference in educating impact between MHC class I alleles. We show that the number and ...

During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into “passive” and “active” based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.