Introduction

Natural killer (NK) cells are defined by the expression of CD16 and CD56 surface molecules. In peripheral blood, two populations of NK cells are present. One population comprises large granular lymphocytes that are phenotyped as CD3–, CD16+, CD56+, and CD94+ cells. Since they do not express T or B cell markers, they are considered to be of a third lymphocyte lineage. The second population of NK cells comprises T cells that express both T cell and NK cell markers (CD3+, CD16+, CD56+ or CD3+, CD16–, CD56+). These cells are known as natural killer T cells (NKT cells) to differentiate them from large granular lymphocytes.

NK and NKT cells have different functions. NK cells are part of the innate cell-mediated response to infected or tumor cells. They recognize and lyse cells with downregulated human leukocyte antigen (HLA) class I molecules. In contrast to classic NK cells, NKT cells have limited cytolytic capability and require antigen presentation. Emerging evidence also suggests that NKT cells are involved in immediate allergic reactions, suppression of auto-reactive lymphocytes, and tumor immunity. Activation or inhibition of NK and NKT cells is dictated by interactions between cell receptors and HLA class IB molecules or CD1 molecules on target cells.

Natural Killer Cell Receptors

Target Cell Recognition Molecules

NK cells do not detect aberrant or infected cells. Rather, they recognize cells that lack HLA class I molecules. This observation has led to the development of the “missing self” hypothesis of NK cell activation. The hypothesis suggests that NK cells can kill normal cells but are prevented from doing so by the presence of inhibitory factors such as HLA class I markers. Downregulation of class I molecules allows NK cells to engage other molecules that either activate or inhibit the NK cell.