KLRF2 encodes NKp65, a C-type lectin-like receptor (CTLR) expressed selectively by innate lymphoid cells group 3 (ILC3) that mediates immune surveillance of human skin 1. NKp65 functions as a high-affinity receptor for keratinocyte-associated C-type lectin (KACL), which is predominantly expressed on keratinocytes 2. Upon KACL engagement, NKp65 triggers NK cell degranulation and cytokine secretion through a hemITAM-dependent signaling mechanism 3. The receptor forms homodimers and undergoes phosphotyrosinylation at a critical tyrosine residue within its hemITAM motif, activating downstream signaling through Syk kinase without direct Syk recruitment 3. Functionally, NKp65-KACL interaction promotes cellular cytotoxicity against KACL-expressing target cells 2. A common polymorphism (rs576601) in KLRF2 results in Pro131Thr substitution, significantly reducing NKp65 surface expression through enhanced intracellular retention, diminishing ligand-binding affinity and substantially impairing cytotoxic function 4. This polymorphism may impact skin immunosurveillance by affecting ILC3-mediated recognition of keratinocytes 4. NKp65-KACL-expressing fibroblasts also orchestrate immune crosstalk controlling squamous cell carcinoma invasion, a mechanism compromised in xeroderma pigmentosum 5.