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Regulation of natural killer cells: analog peptide handshake goes digital.

As an immunology graduate student, I fondly remember Tak Mak likening the T-cell receptor (TCR) to an outstretched hand interrogating each major histocompatibility complex (MHC) antigen it encountered for tactile evidence of viral subversion. Through many series of thoughtful experiments and ultimately, X-ray crystallography, the molecular basis for T-cell specificity and MHC restriction was revealed. This reinforced the distinction between natural killer (NK) cells and T cells and the sophistication of TCR selection and recognition processes elevated T cells into a more advanced evolutionary niche. Immunology texts referenced ‘missing self ’ as key to NK cell function, a model which has expanded into integration of multiple positive and negative signals determining the outcome of NK cell engagement. Discovery of antigenic specificity for murine cytomegalovirus and possibly other antigens, evidence of memory and expanding knowledge of their regulation by killer cell immunoglobulin like receptors (KIR) has forced re-evaluation of NK cell nature [1]. Ironically, the longstanding illusion of MHC-independence segregating them from T cells has given way to indicate a surprisingly consistent focus on the same MHC molecules.