The Early Days of NK Cells: An Example of How a Phenomenon Led to Detection of a Novel Immune Receptor System – Lessons from a Rat Model

Abstract

In this review, I summarize some of the early research on NK cell biology and function that led to the discovery of a totally new receptor system for polymorphic MHC class I molecules. That NK cells both could recognize and kill tumor cells but also normal hematopoietic cells through expression of MHC class I molecules found a unifying explanation in the “missing self” hypothesis. This initiated a whole new area of leukocyte receptor research. The common underlying mechanism was that NK cells expressed receptors that were inhibited by recognition of unmodified “self” MHC-I molecules. This could explain both the killing of tumor cells with poor expression of MHC-I molecules and hybrid resistance, i.e., that F1 hybrid mice sometimes could reject parental bone marrow cells. However, a contrasting phenomenon termed allogeneic lymphocyte cytotoxicity in rats gave strong evidence that some of these receptors were activated rather than inhibited by recognition of polymorphic MHC-I. This was soon followed by molecular identification of both inhibitory and stimulatory Ly49 receptors in mice and rats and killer cell immunoglobulin-like receptors in humans that could be either inhibited or activated when recognizing their cognate MHC-I ligand. Since most of these receptors now have been molecularly characterized, their ligands and the intracellular pathways leading to activation or inhibition identified, we still lack a more complete understanding of how the repertoire of activating and inhibitory receptors is formed and how interactions between these receptors for MHC-I molecules on a single NK cell are integrated to generate a productive immune response. Although several NK receptor systems have been characterized that recognize MHC-I or MHC-like molecules, I here concentrate on the repertoires of NK receptors encoded by the natural killer cell gene complex and designed to recognize polymorphic MHC-I molecules in rodents, i.e., Ly49 (KLRA) receptors.

Novel Targeting to XCR1+ Dendritic Cells Using Allogeneic T Cells for Polytopical Antibody Responses in the Lymph Nodes

“…These results suggest that donor T cells were killed by recruited NK cells in the T cell areas prior to phagocytosis. Killing of allogeneic T cells by NK cells is well documented in humans as well as in rats (42).…”

The Toll-Like Receptor 3 Agonist Polyriboinosinic Polyribocytidylic Acid Increases the Numbers of NK Cells with Distinct Phenotype in the Liver of B6 Mice

“…They are able to differentiate between such cells and normal cells, and therefore spare normal cells [1][2][3]. Other characteristics that are also attributed to NK cells include the release of cytokines and chemokines that are vital for the instigation and amplification of an inflammatory response [4][5][6]. Such chemokines and cytokines include TNF-α, IFN-γ, IL-10, GM-CSF, and IL-13 [4][5][6].…”

“…Other characteristics that are also attributed to NK cells include the release of cytokines and chemokines that are vital for the instigation and amplification of an inflammatory response [4][5][6]. Such chemokines and cytokines include TNF-α, IFN-γ, IL-10, GM-CSF, and IL-13 [4][5][6]. Such functions of NK cells may help understand the essential role played by these cells in conducting immune surveillance against tumours and in the eradication of circulating cancer cells in mice [2,5,7].…”

Listeria monocytogenes infection enhances the interaction between rat non-classical MHC-Ib molecule and Ly49 receptors

“…11 The contents of the class I RT1-CE cluster vary considerably between different rat haplotypes. 9,12…”