We characterized the murine NK cell subsets of the tumor microenvironment （TME） with low expressions of CD16 and NKG2D and investigated the chemokines that deter CD 16~~w NKG2Dl^w subsets. Our results demonstrated t...We characterized the murine NK cell subsets of the tumor microenvironment （TME） with low expressions of CD16 and NKG2D and investigated the chemokines that deter CD 16~~w NKG2Dl^w subsets. Our results demonstrated the activation of primary and KY- 1 NK cell by ligands and found that exogenous CXCL10/interferon-gamma-induced protein 10 （IP-10） and fractalkine （FKN） can up-regulate the expression of CD 16 and NKG2D. Moreover, both IP-10 and FKN are shown to facilitate migration, adhesion and cyto- toxicity of NK cell subsets of the TME, due to the up-regu- lated CD16 and NKG2D. Overall, our data provide a new path by which to enhance murine NK cell cytotoxic potential and improve the quality of NK cells of the TME.展开更多
Signaling lymphocytic activation molecule （SLAM）-associated protein （SAP） is a Src homology （SH） domain 2-containing in- tracellular adaptor protein that is predominantly expressed in the hematopoietic system by...Signaling lymphocytic activation molecule （SLAM）-associated protein （SAP） is a Src homology （SH） domain 2-containing in- tracellular adaptor protein that is predominantly expressed in the hematopoietic system by T lymphocytes and NK cells. SAP protein is encoded by the SH2DIA gene located on the X chromosome. Loss-of-function mutations in SAP cause the X-linked lymphoproliferative disease （XLP）, a severe immunodeficiency characterized by heightened susceptibility to Epstein-Barr vi- rus and impaired humoral immunity. Normal individuals express several functional and non-functional isoforms of SAP as a result of alternative splicing. In this study, we identify a cryptic exon in the murine Sh2dla gene. At the mRNA level, the new isoform of SAP （SAP-2） that includes this new exon is widely expressed in lymphoid tissues by C57BL/6 and 129 strains of inbred mice. SAP-2 accounts for approximately 1%-3% of total SAP transcripts, and it is dynamically regulated during lym- phocyte activation. At the protein level, the SAP-2 isoform is a 144 amino-acid protein. Compared to the dominant 126 ami- no-acid SAP-I isoform, the additional 18 amino acids are inserted into a structural region that is critical for phosphotyrosine binding. Our functional analysis in vitro indicates that SAP-2 is a non-functional isoform due to decreased protein stability. Thus, both human and mouse have multiple SAP splice isoforms that may or may not function. Modulation of relative propor- tions of these isoforms is potentially a mechanism whereby cells can regulate SAP-mediated biological activities.展开更多
基金the National Natural Science Foundation of China (81171975)the Tianjin Institutes for Basic Sciences (15JCYBJC26900)
文摘We characterized the murine NK cell subsets of the tumor microenvironment （TME） with low expressions of CD16 and NKG2D and investigated the chemokines that deter CD 16~~w NKG2Dl^w subsets. Our results demonstrated the activation of primary and KY- 1 NK cell by ligands and found that exogenous CXCL10/interferon-gamma-induced protein 10 （IP-10） and fractalkine （FKN） can up-regulate the expression of CD 16 and NKG2D. Moreover, both IP-10 and FKN are shown to facilitate migration, adhesion and cyto- toxicity of NK cell subsets of the TME, due to the up-regu- lated CD16 and NKG2D. Overall, our data provide a new path by which to enhance murine NK cell cytotoxic potential and improve the quality of NK cells of the TME.
基金supported by funds from the Tsing-hua-Peking Center for Life Sciencesthe National Natural Science Foundation of China(81072464)
文摘Signaling lymphocytic activation molecule （SLAM）-associated protein （SAP） is a Src homology （SH） domain 2-containing in- tracellular adaptor protein that is predominantly expressed in the hematopoietic system by T lymphocytes and NK cells. SAP protein is encoded by the SH2DIA gene located on the X chromosome. Loss-of-function mutations in SAP cause the X-linked lymphoproliferative disease （XLP）, a severe immunodeficiency characterized by heightened susceptibility to Epstein-Barr vi- rus and impaired humoral immunity. Normal individuals express several functional and non-functional isoforms of SAP as a result of alternative splicing. In this study, we identify a cryptic exon in the murine Sh2dla gene. At the mRNA level, the new isoform of SAP （SAP-2） that includes this new exon is widely expressed in lymphoid tissues by C57BL/6 and 129 strains of inbred mice. SAP-2 accounts for approximately 1%-3% of total SAP transcripts, and it is dynamically regulated during lym- phocyte activation. At the protein level, the SAP-2 isoform is a 144 amino-acid protein. Compared to the dominant 126 ami- no-acid SAP-I isoform, the additional 18 amino acids are inserted into a structural region that is critical for phosphotyrosine binding. Our functional analysis in vitro indicates that SAP-2 is a non-functional isoform due to decreased protein stability. Thus, both human and mouse have multiple SAP splice isoforms that may or may not function. Modulation of relative propor- tions of these isoforms is potentially a mechanism whereby cells can regulate SAP-mediated biological activities.
