Lineage relationships of human interleukin-22-producing CD56+ RORγt+ innate lymphoid cells and conventional natural killer cells

Human interleukin (IL)-22-producing ROR gamma t(+) innate lymphoid cells (ILC22) and conventional natural killer (cNK) cells are present in secondary lymphoid tissues. Both have an immunophenotype corresponding to stage III NK progenitors (CD56(+/-) CD117(high)CD94(-)). Using an in vitro differentiation and primary human tissues, we investigated their developmental relationships. cNK cells showed a CD56(+)CD117(+)CD7(+/-) LFA-1(high) phenotype and expressed surface receptors, cytokines, and transcription factors found on mature cNK cells. In contrast, ILC22 cells were contained within the CD56(+)CD117(high)CD94(-)CD7(-)LFA-1(-) fraction and produced IL-22, IL-8, and granulocyte macrophage colony stimulating factor. Although ILC22 cells expressed NKp44 and CD161, they lacked most other NK receptors and NK-associated transcription factors (T-bet and Eomes) and were incapable of interferon-gamma production or cytotoxic responses. Most purified CD56(+)CD117(+)CD7(+/-) LFA-1(-) remained as ILC22 cells and never became cNK cells. In the absence of IL-15, CD34(+) cells showed a complete block in cNK differentiation and instead gave rise to a CD56(+) population of ILC22 cells. Conversely, in the absence of IL-7 and stem cell factor, cNK cells were generated but ILC22 cells showed minimal differentiation. Although human ILC22 cells and cNK progenitors have a phenotype that overlaps with stage III NK progenitors, they have unique cytokine requirements and can be distinguished by LFA-1 expression.