Selective rejection of H–2-deficient lymphoma variants suggests alternative immune defence strategy

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.

Killer Ig-like receptor (KIR) genotype and HLA ligand combinations in ulcerative colitis susceptibility

“…NK cells display variegated expression of both activating and inhibitory receptors, their effector responses governed by the resulting balance of signalling. As most NK cells are believed to express at least one inhibitory receptor to self, 45,46 an individual possessing both KIR2DL3 and HLA-C1 is likely to have NK cell subsets which rely on this interaction as the main source of inhibitory signalling. The affinity of KIR2DL3 to its ligand is the weakest known of all inhibitory KIR; 47 therefore, KIR2DL3-positive NK cells may theoretically have a greater potential for activation, leading to possible protective effects in UC.…”

In vivo tumor cell rejection induced by NK cell inhibitory receptor blockade: Maintained tolerance to normal cells even in the presence of IL‐2

“…RMA-S is a TAP-2-deficient variant of RMA, generated by mutagenesis followed by selection for MHC class I deficiency [4,48,49]. The cells were cultured in complete RPMI 1640 (100 U/mL penicillin, 100 mg/mL streptomycin, 2 mM L-glutamine, 50 mM 2-ME (2-mercaptoethanol), 1 mM sodium pyruvate, non-essential aa and 10% heat inactivated FBS) in 7% CO 2 at 371C.…”

“…The outcome of an interaction between an NK cell and a target cell is determined by integration of activating and inhibitory signals. Inhibitory NK receptors prevent NK cells from eliminating syngeneic, normal cells expressing MHC class I, but allow rejection of cells lacking cognate MHC class I ligands in accordance with the ''missing-self'' hypothesis [4,5]. Numerous types of activating receptors are expressed by mouse NK cells, for example NKG2D, Ly49D, NKp46 (NCR1, MAR-1) and NKR-P1C (NK1.1) [6][7][8][9][10].…”

“…Studies in mice demonstrated that NK cells vigorously reject both neoplastic and normal, healthy cells lacking one or more self MHC class I ligands [4,5,[21][22][23]. Adoptive transfer of activated NK cells with missing-self-reactivity against the host can reduce GVH disease, promote BM engraftment and provide graft-versustumor responses [24,25].…”

Genetic identity and differential expression of p38.5 (Haymaker) in human malignant and nonmalignant cells

“…NK cells are an important cellular component of the innate immune system 4,5 that are capable of destroying certain malignant cells without prior antigenic stimulation. 6,7 Further studies suggested that p38.5 might play a role in naive NK cell-mediated destruction of hematopoetic tumor cells since the protein specifically bound to NK cells (but not to T lymphocytes) and preincubation of NK cells with the purified protein inhibited cytotoxicity. 3 The purpose of the current study was to complete the analysis of the sequence of the 38.5 kD protein and to determine its expression in malignant and nonmalignant cells of different tissue origins.…”