Distinct developmental pathways generate functionally distinct populations of natural killer cells.

Area of Science:

• Immunology
• Cell Biology
• Developmental Biology

Background:

• Natural killer (NK) cells are crucial for eliminating virus-infected and tumor cells.
• NK cell development typically involves common precursors with other innate lymphoid cells (ILCs).

Purpose of the Study:

• To identify and characterize distinct NK cell developmental pathways.
• To investigate the functional differences between NK cells derived from separate precursors.
• To explore the conservation of these pathways in human NK cells.

Main Methods:

• Identification of a novel early NK progenitor (ENKP) population.
• Transcriptional profiling of ENKP-derived NK cells (ENKP_NK) and ILCP-derived NK cells (ILCP_NK).
• Development of surface marker combinations for isolating ENKP_NK and ILCP_NK populations in mice.
• Functional assays assessing NK cell responses to viral and bacterial infections.

Main Results:

• ENKPs generate NK cells independently of ILCPs, with distinct transcriptional profiles.
• Specific surface markers successfully isolated ENKP_NK and ILCP_NK subsets.
• ENKP-derived NK cells are key responders to mouse cytomegalovirus, while ILCP-derived NK cells are superior IFNγ producers against Salmonella and herpes simplex virus.
• Human CD56^dim and CD56^bright NK cells show transcriptional similarities to mouse ENKP_NK and ILCP_NK cells, respectively.

Conclusions:

• Two distinct developmental pathways for NK cells exist in mice, originating from ENKPs and ILCPs.
• These pathways generate functionally specialized NK cell subsets with differential roles in immunity.
• Evidence suggests these distinct NK cell development pathways are conserved in humans.