Catherine Blish, PhD
Coordinated regulation of natural killer receptor expression in the maturing human immune system
Stanford University School of Medicine
Medicine & Immunology
Natural killer (NK) cells are responsible for recognizing and killing transformed, stressed, and infected cells. They recognize a set of non-antigen-specific features collectively termed “altered self”. This is achieved through balanced combinatorial signals from a collection of activating and inhibitory receptors. These natural killer cell receptors (NKR) are also expressed on CD4+ and CD8+ T cells, B cells, and monocytes, though little is known about the factors that influence their expression across different subsets. Using mass cytometry, we found that NKR expression patterns distinguished these cell types in human peripheral blood. In individuals with high levels of CD57, indicative of a mature immune repertoire, NKR lost fidelity for NK cells. They were instead found in increasing proportions on other cell subsets, especially on CD8+ T cells. Mature NK and CD8+ T cell populations showed increased diversity of NKR surface expression patterns, but their determinants were distinct. Mature NK cells acquired primarily inhibitory receptors. By contrast, CD8+ T cells attained a specific subset of both activating and inhibitory receptors, potentially imbuing them with a distinct functional role in the immune response. Concurrently, monocytes showed decreased expression of the generalized inhibitory receptor LILRB1, consistent with an increased activation threshold. Therefore, the expression of NKR is coordinately regulated as the immune system matures, resulting in the transfer of altered self recognition potential among divergent cell types. This coordinated regulation likely reduces antigen specificity in the mature human immune system, and has important implications for vaccine and therapeutic design in the setting of aging and chronic infection.