Abstract
Natural killer (NK) lymphocytes are part of the innate immune system and are important in immune protection against tumourigenesis. NK cells display a broad repertoire of activating and inhibitory cell surface receptors that regulate NK cell activity. The Ly49 family of NK receptors is composed of several members that recognize major histocompatibility complex class I (MHC-I) or MHC-I-related molecules. Ly49E is a unique inhibitory member, being triggered by the non-MHC-I-related protein urokinase plasminogen activator (uPA) in contrast to the known MHC-I-triggering of the other inhibitory Ly49 receptors. Ly49E also has an uncommon expression pattern on NK cells, including high expression on liver DX5− NK cells. Furthermore, Ly49E is the only Ly49 member expressed by epidermal γδ T cells. As γδ T cells and/or NK cells have been shown to be involved in the regulation of cutaneous, pulmonary and liver malignancies, and as uPA is involved in tumourigenesis, we investigated the role of the inhibitory Ly49E receptor in the anti-tumour immune response. We demonstrate that, although Ly49E is highly expressed on epidermal γδ T cells and liver NK cells, this receptor does not play a major role in the control of skin tumour formation or in lung and liver tumour development.
Highlights
T cells present in thymus and peripheral lymphoid organs have a large repertoire of T cell receptors (TCRs) composed of either αβ or γδ heterodimers
The regulatory role of natural killer (NK) receptors in the anti-tumour immune response has been most extensively studied for NKG2D, a dominant activating receptor present on almost all NK cells and on part of γδ T cells
Analysis of NKG2D ligand expression in tumours from both strains showed that early tumours of WT mice lack NKG2D ligands, while these ligands are present in NKG2D-deficient mice
Summary
T cells present in thymus and peripheral lymphoid organs have a large repertoire of T cell receptors (TCRs) composed of either αβ or γδ heterodimers. They demonstrated that γδ T cells play a critical role in the protective immune response against tumour development through provision of an early source of IFN-γ, that in turn regulates the function of tumour-specific αβ T cells This was shown by analysis of tumour formation and growth in C57BL/6 TCR δ−/− compared to WT mice upon either intradermal injection of 3-MCA or subcutaneous injection of B16 melanoma www.nature.com/scientificreports/. Plasmin belongs to the serine proteases and has a wide range of functions both in non-pathological processes, such as tissue remodelling and wound healing, and in pathological conditions, including tumour growth and metastasis It contributes to tumour development by its ability to cleave and activate precursor forms of certain matrix metalloproteases that degrade many extracellular matrix components, a crucial step in cancer invasion and metastasis[19]. Our hypothesis is that the Ly49E receptor, triggered by uPA produced by tumour cells, inhibits immune subpopulations involved in the anti-tumour response, thereby revealing a novel tumour immune escape mechanism
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