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Review
. 2019 Jul:204:3-13.
doi: 10.1016/j.clim.2018.10.013. Epub 2018 Oct 23.

SLAMF6 in health and disease: Implications for therapeutic targeting

Burcu Yigit  1 , Ninghai Wang  2 , Roland W Herzog  3 , Cox Terhorst  4
Affiliations
Review

SLAMF6 in health and disease: Implications for therapeutic targeting

Burcu Yigit et al. Clin Immunol. 2019 Jul.
No abstract available

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Figures

Figure 1.
Figure 1.
Signaling lymphocyte activation molecule family (SLAMF) of genes and protein. a. Organizational overview of SLAMF gene cluster on chromosome 1 in human and mouse. b. SLAMF members consist of an IgV/IgC2 ectodomain, which is duplicated in SLAMF3. While SLAMF2 and SLAMF4 bind each other, other SLAMF receptors are homophilic. Six members of the family contain varying lengths of cytoplasmic tail with ITSM motifs (Y) that can recruit and bind the adaptors SAP and/or EAT-2.
Figure 2.
Figure 2.
Homophilic engagement of SLAMF3, SLAMF5 and SLAMF6 occurs via interactions of the IgV domains. Specificity of homophilic binding is determined by different surface characteristics. All three SLAMF receptors show different binding affinities. Green = hydrophobic, red= hydrophilic amino acids
Figure 3.
Figure 3.. Ribbon diagram showing SAP/SLAMF1 pY281 complex.
The bound SLAMF1 phosphopeptide is shown in a stick representation (yellow). Selected SAP residues that form the binding site are shown in blue. SLAMF1 residues N-terminal to pY281 make additional interactions with SAP at pY −3 and pY −1 (positions relative to pTyr281)[34, 35].
Figure 4.
Figure 4.. SAP couples Fyn to SLAMF receptors.
SAP binds the Fyn SH3 domain through a non-canonical surface interaction (zoomed area). SLAM peptide binds SAP in a 3-pronged mode by via the b-strand of N-terminal, Tyr 281 and Val 284.
Figure 5.
Figure 5.
SLAMF6 localizes at the immune synapse. Ligation of SLAMF6 on a T cell recruits binding of SAP to the ITSM on the cytoplasmic tail. SAP recruits Fyn and induces activation. SAP has the highest affinity for cytoplasmic tail of SLAMs and blocks binding of SHP-1/2. In the absence of SAP, SHP-1/2 binds to cytoplasmic tail of SLAMF6 and induces negative signaling on T cells [126]. B cells do not express SAP. Whether EAT-2 is expressed or it blocks recruitment of SHP-1/2 is not known. However, ligation of SLAMF6 with an antibody in B cells appear to induce negative signals, which may be due to binding of SHP-1/2.
Figure 6.
Figure 6.. The CLL Microenvironment.
Contact between CLL cells and nurse like cells (NLCs) is established by chemokine receptors and adhesion molecules expressed on CLL cells and ligands on NLCs. The CD38-CD31 axis promotes CLL survival. CXCR4/CXCL12 chemokine gradient allows shuffling of CLL cells between circulation and secondary lymphoid organs to receive survival and proliferation signals. SLAMF5 and SLAMF6 are expressed on the surface of NLCs (Yigit, unpublished data). The relevant contribution of these receptors to CLL survival requires further investigation. T cells are another major contributor to CLL survival. Secretion of chemokines CCL3/4 by CLL cells attracts T cells nearby. CD40/CD40L interaction promotes survival and PD-1/PD-L1 pathway favors immune evasion of CLL cells. NK cells, bone marrow stromal cells (BMSCs) and follicular dendritic cells (FDCs) also contribute to CLL survival.
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