The NKp44-1 Isoform Is an Activating Receptor for PDGF-DD Expressed on Natural Killer Cells

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Natural killer (NK) cells are crucial for tumor surveillance, utilizing surface receptors to regulate their activity.
• The NKp44 receptor, induced by IL-2/IL-15, recognizes platelet-derived growth factor D (PDGF-DD) and exists in three isoforms (NKp44-1, -2, -3) with distinct signaling potentials.
• NKp44-1's role is ambiguous due to a tyrosine residue (Y238) potentially mediating inhibition, and its expression and signaling upon PDGF-DD engagement remain uncharacterized.

Purpose of the Study:

• To define the expression and signaling properties of NKp44 isoforms in response to PDGF-DD.
• To investigate whether NKp44-1 mediates inhibitory or activating signals upon PDGF-DD engagement.
• To determine the role of the Y238 residue in NKp44-1 signaling.

Main Methods:

• Utilized C-terminal targeting monoclonal antibodies (mAbs) to detect NKp44 protein expression.
• Employed a NFAT-GFP reporter system to assess NKp44 signaling.
• Studied IL-2 expanded NK cells stimulated with PDGF-DD.

Main Results:

• Demonstrated protein expression of NKp44-1 and NKp44-2/3 isoforms in IL-2 expanded NK cells.
• Showed that NKp44-1 signaling upon PDGF-DD engagement is activating, though weaker than NKp44-3.
• Found that the Y238 residue is dispensable for NKp44-1 activating signals and functions as an internalization motif.

Conclusions:

• Provided the first evidence for NKp44 isoform expression in NK cells.
• Established that PDGF-DD activates NKp44-1 signaling independently of Y238.
• Laid the groundwork for future research into how NKp44 isoform-specific PDGF-DD sensing influences immune functions.