Human Lymphoid Tissues Harbor a Distinct CD69+CXCR6+ NK Cell Population

Abstract Knowledge of human NK cells is based primarily on conventional CD56bright and CD56dim NK cells from blood. However, most cellular immune interactions occur in lymphoid organs. Based on the coexpression of CD69 and CXCR6, we identified a third major NK cell subset in lymphoid tissues. This population represents 30–60% of NK cells in marrow, spleen, and lymph node but is absent from blood. CD69+CXCR6+ lymphoid tissue NK cells have an intermediate expression of CD56 and high expression of NKp46 and ICAM-1. In contrast to circulating NK cells, they have a bimodal expression of the activating receptor DNAX accessory molecule 1. CD69+CXCR6+ NK cells do not express the early markers c-kit and IL-7Rα, nor killer cell Ig-like receptors or other late-differentiation markers. After cytokine stimulation, CD69+CXCR6+ NK cells produce IFN-γ at levels comparable to CD56dim NK cells. They constitutively express perforin but require preactivation to express granzyme B and exert cytotoxicity. After hematopoietic stem cell transplantation, CD69+CXCR6+ lymphoid tissue NK cells do not exhibit the hyperexpansion observed for both conventional NK cell populations. CD69+CXCR6+ NK cells constitute a separate NK cell population with a distinct phenotype and function. The identification of this NK cell population in lymphoid tissues provides tools to further evaluate the cellular interactions and role of NK cells in human immunity.