A Novel Human CD34(+) Subset That Constitutively Expresses the High Affinity Interleukin-2 Receptor Traffics to Lymph Nodes and Differentiates into CD56^Bright Natural Killer Cells.

In adult humans, T cells differentiate in the thymus and B cells develop in the bone marrow, but the site(s) of natural killer (NK) cell differentiation are unclear. Here we describe, for the first time, a unique CD34(+) population found in human lymph nodes (LN) that differentiates into NK cells. CD56^bright NK cells represent <10% of NK cells in peripheral blood (PB) yet predominate in LN where they can compete for endogenous T cell-derived IL-2 during immune activation due to their unique expression of functional high affinity (HA) interleukin (IL)-2 receptors (IL-2R). We hypothesized that a subset of CD34(+) hematopoietic precursor cells (HPC) might also express functional HA IL-2R and potentially differentiate into CD56^bright NK cells via activation with low dose IL-2. We first identified a novel human CD34^dimCD45RA(+) HPC in PB with constitutive expression of the HA IL-2R. When cultured in picomolar concentrations of IL-2 that selectively saturate the HA IL-2R, these cells give rise to CD56^bright NK cells, and this effect is blocked when IL-2 cannot bind to its HA receptor. This unique CD34(+) population expresses IL-2Rα, CD2, CD7, c-kit, L-selectin, and NKR-P1A, all of which are also expressed by CD56^bright NK cells. Unique among total PB CD34(+) cells, this novel population displays high integrin α₄β₇ expression. This attribute, in addition to its high L-selectin expression, suggested that these cells may traffic to LN where their progeny, CD56^bright NK cells, represent the major NK subset. Indeed we found a distinct CD34^dimCD45RA(+)α₄β₇^bright population that resides in the T cell rich regions of human LN, and when stimulated in vitro with 10 pM IL-2, this cell gives rise to CD56^bright NK cells. This novel population represents only ~6% of all PB CD34(+) HPC yet is the major if not exclusive CD34(+) subset in LN. While murine studies strongly support the notion that most if not all NK cells require IL-15 for their development, these new human data suggest a model for development of a minor human NK subset, the CD56^bright NK cells, whereby CD34^dimCD45RA(+)α₄β₇^bright HPC constitutively expressing the HA IL-2R traffic to peripheral LN where endogenous T cell-derived IL-2 can drive CD56^bright NK cell differentiation in vivo.