NKG2D is an activating receptor expressed on all human NK cells and a subset of T cells. In cytolytic conjugates between NK cells and target cells expressing its ligand MHC class I chain-related gene A, NKG2D accumulates at the immunological synapse with GM1-rich microdomains. Furthermore, NKG2D is specifically recruited to detergent-resistant membrane fractions upon ligation. However, in the presence of a strong inhibitory stimulus, NKG2D-mediated cytotoxicity can be intercepted, and recruitment of NKG2D to the immunological synapse and detergent-resistant membrane fractions is blocked. Also, downstream phosphorylation of Vav-1 triggered by NKG2D ligation is circumvented by coengaging inhibitory receptors. Thus, we propose that one way in which inhibitory signaling can control NKG2D-mediated activation is by blocking its recruitment to GM1-rich membrane domains. The accumulation of activating NK cell receptors in GM1-rich microdomains may provide the necessary platform from which stimulatory signals can proceed.

The adapter protein SAP is important for the signal transduction of the family of SLAMrelated receptors (SRR), which have important immune-modulating functions. The importance of SAP and SRR for a functional immune reaction becomes obvious in patients suffering from X-linked lymphoproliferative disease, which is characterized by non-functional SAP. Here we investigate the regulation of SAP expression in human NK cells. We demonstrate that SAP mRNA expression and protein levels are low in freshly isolated resting NK cells. IL-2 stimulation leads to an up-regulation of SAP expression, which can be enhanced by IL-12, the stimulation of TLR3 by polyinosinic-polycytidylic acid (poly(I:C))and to a lesser extent by IFN-a. EAT-2, a SAP-related adapter protein, is already detectable in resting NK cells and does not change its expression after IL-2 stimulation. The regulation of SAP has functional consequences for the stimulation of NK cell cytotoxicity by 2B4. In resting NK cells, 2B4 stimulation can only enhance NK cell lysis when co-triggered with other activating NK cell receptors. In IL-2-activated NK cells with high SAP expression the triggering of 2B4 alone is sufficient to induce NK cell cytotoxicity, demonstrating a correlation between the regulated SAP expression and the function of 2B4. IntroductionNatural killer (NK) cells represent the first line of defense against stressed, virally infected and malignant cells. The major effector functions of NK cells are cytotoxicity and cytokine release. These responses are regulated by different activating and inhibitory surface receptors [1]. One emerging group of activating NK cell receptors encompasses cell surface molecules of the recently identified family of signaling lymphocyte activation molecule (SLAM)-related receptors (SRR) [2]. This group of Ig-like receptors includes 2B4 (CD244), SLAM (CD150), CD84, Ly-9 (CD229), NTB-A (Ly-108) and CD2-like receptor activating cytotoxic cells (CRACC, CS-1, CD319). 2B4 is expressed on human NK cells, cytotoxic CD8 + T cells, cd T cells and on resting monocytes, eosinophils and basophiles. The cytoplasmic tail of 2B4 contains four immunoreceptor tyrosinebased switch motifs (ITSM). Once phosphorylated, the immunoreceptor tyrosine-based switch motifs of 2B4 can recruit several signaling molecules including SLAMassociated protein (SAP), SHP-1, SHP-2, SHIP, EAT-2 (also called SH2D1B), .The ligand of 2B4 is CD48, a member of the CD2 family of Ig-like receptors, which is expressed on many cell types of the hematopoietic system [8,9] [13]. SAP can function as a natural blocker of SH2 domain-mediated interactions and might therefore prevent the interactions between SHP-2 and possibly SHP-1 with 2B4 [3,7,14], explaining why 2B4 can mediate inhibitory signals in the absence of SAP. SAP is also involved in the positive signaling by 2B4 and other SRR by recruiting and activating the Src family kinase Fyn through an unusual SH2-SH3 domain interaction [15,16].Infection with murine CMV or lymphocytic choriomeningitis virus leads to an up-regu...

The modulation of antigen receptor signals is important for a productive immune response. The main function of the recently identified members of the signaling lymphocyte activating molecule (SLAM)-related receptors (SRR) is the fine-tuning of immune cell activation. Disruption of SRR function is the cause for severe immune disorders such as X-linked lymphoproliferative syndrome (XLP), where XLP patients carry a mutation in SLAM-associated protein (SAP) (SH2D1A), an important adaptor molecule for the signal transduction of SRR. Recent data also suggest that SRR may play a role in autoimmune diseases and the function of hematopoietic stem and progenitor cells. Here, we review the current understanding of SRR function in different immune cells.

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