C-type lectin-like NKC-encoded immunoreceptors NKp80 and NKp65 are selectively expressed by human innate lymphocyte subsets, uniquely signal via hemITAMs and facilitate tissue-specific immunosurveillance via their genetically linked ligands AICL and KACL

Abstract

Abstract NKp80 is an activating C-type lectin-like immunoreceptor (CTLR) on human NK cells. Upon ligation by its cognate ligand ‘activation-induced C-type lectin’ (AICL) up-regulated on PAMP-stimulated myeloid cells and interleukin-experienced NK cells, NKp80 stimulates NK cytotoxicity and cytokine secretion. Unlike other NK receptors, NKp80 uses an atypical cytoplasmic hemITAM for cellular activation. In contrast to “classical” hemITAMs of related myeloid CTLR, we showed that the NKp80 hemITAM does not recruit Syk upon phosphorylation. However, we now provide evidence for specific recruitment of other signaling molecules by NKp80. Alike its close relative NKp80, NKp65 is a homodimeric CTLR with a cytoplasmic hemITAM and encoded in the Natural Killer Gene Complex (NKC). NKp65 binds with high affinity to its cognate genetically linked ligand KACL almost exclusively expressed by human keratinocytes. We previously showed that NKp65/KACL interaction activates cytotoxicity by NK-92 cells. However, while NKp80 is expressed by virtually all human NK cells, physiological expression of NKp65 remained elusive. Generation of NKp65-specific mAb enabled us to trace NKp65 expression to a minor subset of human innate lymphocytes. Transcriptomics revealed strict correlation between NKp65 expression ILC hallmark genes. Hence, NKp65 expression defines that ILC subset and enables a tissue-specific cross-talk with human keratinocytes. Moreover, we show that NKp80 and NKp65 are mutually exclusive expressed by NK cells and that ILC subset, qualifying NKp80 and NKp65 as markers of these 2 distinct innate lymphocyte lineages and raising questions for their respective subset-associated function.