Inhibitory receptors of natural killer cells : specificity and regulation

Abstract

Immunological surveillance of organs and tissues for pathogens and transformed cells by immune cells and their soluble mediators is of outmost importance for the well-being of the host. The natural killer (NK) cell is an example of such an immune cell. Experimental and clinical studies have demonstrated that NK cells are able to fulfill a number of different functions such as elimination of various micro-organisms and rejection of tumor cells. Evidence from studies of in vivo transplantation of bone marrow cell grafts and lymphomas as well as lysis of tumor cell targets in vitro suggests that MHC class I molecules play an important role in NK cell function. In support of this, NK cells have been demonstrated to express activating as well as inhibitory MHC class I specific receptors. These receptors are of two general types, encoded either by the C-type lectin or immunoglobulin superfamily of genes. Such specific inhibitory receptors for normal self-molecules can determine NK specificity by dominantly inhibiting activation signals initiated by broadly reactive, triggering receptors.

The aim of the work presented in this thesis was to study MHC class I mediated regulation of murine NK cells, with respect to specificity and expression of inhibitory Ly49 receptors in the C-type lectin superfamily. In paper I, we used IL-2 activated NK cells from MHC (H-2Dd) transgenic mice to demonstrate that there is an MHC class I allele specific protection of lymphoblast targets against NK cell lysis in vitro. This influence was less clear with tumor targets. Furthermore, MHC haplotypes with different class I alleles were able to confer similar protection against NK cells lysis suggesting that some MHC class I molecules share structural "motifs" involved in the recognition of NK cells. This was followed up in paper IV, in which we analysed this cross-reactivity between two different H-2D alleles, H-2Dd and H-2Dp. We concluded that these two alleles alter NK specificity in a similar but not identical manner. An explanation for this, based on cross-reactivity at the receptor level, was provided in paper V: the NK cell inhibitory receptor Ly49A recognizes both H-2Dd and H-2Dp.

A major theme in the thesis is the influence of host MHC class I molecules on NK cell receptors and function. In paper II we demonstrated that the expression of the NK cell inhibitory receptor Ly49A is downregulated in ligand (H-2Dd) expressing hosts, with functional consequences: NK cells expressing low levels of Ly49A receptors were less efficiently inhibited by cells expressing the relevant MHC class 1 ligands compared to NK cells with high Ly49A expression (paper II and III). A "receptor calibration" model is proposed to explain the functional relevance of reduced expression of inhibitory receptors. This model is based on the idea that NK cells with fewer inhibitory receptors can discriminate more efficiently between cells with high and reduced (but not deleted) MHC class I expression; the latter can occur in neoplastic as well as infected cells. The implications of "receptor calibration" are discussed, as well as general models for the determination of NK cell receptor repertoire and NK cell self-tolerance.