Natural killer cell receptors and their ligands.

Description

At the opposing end of the spectrum of NK signalling are activating receptors, which require adaptors. One such receptor critical to the immunosurveillance of stressed, transformed and infected cells is NKG2D, previously known to signal through DNAX activating protein 10 (DAP10). We have isolated a novel short isoform of murine NKG2D, which pairs with both DAP10 and DAP12, whereas full-length NKG2D preferentially associates with DAP10. Analyses of isoform transcripts in NK and T cells coupled with the known capacity of these cell types to express DAP10 and DAP12 provide insight into the complex regulation allowing NKG2D to mediate the distinct functions of stimulation in NK cells and co-stimulation in T cells.Natural killer (NK) cell effector functions such as cytotoxicity and cytokine release are determined by the balance of signalling through two functionally opposing types of receptors: inhibitory and activating. Inhibitory receptors, which act to prevent damage to self, signal through an immunoreceptor tyrosine based inhibitory motif (ITIM) within their cytoplasmic tails. We have demonstrated that the rat ITIM-containing receptor, NKR-P1B, isolated using expression cloning, is inhibitory.Along with this duality, an interesting feature of NKG2D is its evolutionary conservation. More typical are the killer immunoglobulin-like receptor (KIR) and Ly49 families which are nearly exclusively found in human and mouse respectively. Strikingly, NKG2D is ∼60% identical in man and mouse, triggering speculation that it may play a role in other fundamental processes. Thus, we examined its ligands (NKG2D-lig) and found them expressed on ∼1/3 of BALB/c thymocytes, which are MHC-Imid. This largely CD4+CD8 + or double positive (DP) cohort likely contains cells that have not yet been acted upon by either selection or neglect. Neglect appears to result in the down-regulation of both NKG2D-lig and MHC-I. This NKG2D-lig low/MHC-Ilow DP subset, containing active caspases, is the first report of the detection of substantial apoptosis during normal T cell development. Alternatively, positive selection may act upon the NKG2D-lig high cohort decreasing NKG2D-lig but increasing MHC-I along with the transition to a single positive state. These data suggest an as yet undefined role for NKG2D in BALB/c T cell development.

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