Quantifying the unanticipated diversity of the human NK cell repertoire (P1456)

Abstract

Abstract Like their T and B lymphocyte counterparts, natural killer (NK) cells exist in small and specialized subpopulations. However, while T and B cell repertoire diversity is generated primarily through DNA rearrangement to produce a single antigen-specific receptor, the diversity of the NK cell repertoire is determined by the expression of a spectrum of activating and inhibitory receptors. To evaluate the human NK cell repertoire on a single-cell basis, we simultaneously measured more than 25 NK cell receptors in the peripheral blood of 22 healthy individuals via mass cytometry. We used Boolean gating to classify cellular phenotypes. Based on the Simpson index, an ecological measure designed to quantify population diversity, we found that total NK cell repertoire diversity was approximately normally distributed across individuals. Using rarefaction curves and non-parametric species estimators, we calculate the expansiveness of the NK cell repertoire at a minimum of 100,000 unique phenotypes. Furthermore, within an individual, the ex vivo addition of the homeostatic cytokine IL-15 biased the repertoire toward highly common and uncommon phenotypes, increasing the total population richness but decreasing the overall diversity. These data show, for the first time, that the receptor-based NK cell repertoire is exquisitely diverse. They further suggest an optimal baseline diversity that is highly sensitive to optimization by exogenous factors.