Ca2+ regulates T-cell receptor activation by modulating the charge property of lipids
Calcium–lipid electrostatic interactions are shown to amplify the tyrosine phosphorylation of CD3ε and CD3ζ in T-cell antigen receptor complex. Calcium control of T cells These authors show that Ca 2+ can regulate the ionic interaction between the T-cell receptor–CD3 complex (TCR) and anionic phosph...
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| Veröffentlicht in: | Nature (London) 2013-01, Vol.493 (7430), p.111-115 |
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| creator | Shi, Xiaoshan Bi, Yunchen Yang, Wei Guo, Xingdong Jiang, Yan Wan, Chanjuan Li, Lunyi Bai, Yibing Guo, Jun Wang, Yujuan Chen, Xiangjun Wu, Bo Sun, Hongbin Liu, Wanli Wang, Junfeng Xu, Chenqi |
| description | Calcium–lipid electrostatic interactions are shown to amplify the tyrosine phosphorylation of CD3ε and CD3ζ in T-cell antigen receptor complex.
Calcium control of T cells
These authors show that Ca
2+
can regulate the ionic interaction between the T-cell receptor–CD3 complex (TCR) and anionic phospholipids — important components in adaptive immunity — by modulating the electrostatic property of phospholipids. Ca
2+
is shown to bind to the phosphate group in anionic phospholipid headgroups and undermines CD3
CD
–membrane ionic interaction, thus facilitating TCR phosphorylation. This positive feedback regulation by Ca
2+
can amplify TCR signalling to potentiate the effector function of T cells against invading pathogens.
Ionic protein–lipid interactions are critical for the structure and function of membrane receptors, ion channels, integrins and many other proteins
1
,
2
,
3
,
4
,
5
,
6
,
7
. However, the regulatory mechanism of these interactions is largely unknown. Here we show that Ca
2+
can bind directly to anionic phospholipids and thus modulate membrane protein function. The activation of T-cell antigen receptor–CD3 complex (TCR), a key membrane receptor for adaptive immunity, is regulated by ionic interactions between positively charged CD3ε/ζ cytoplasmic domains (CD3
CD
) and negatively charged phospholipids in the plasma membrane
1
,
8
,
9
,
10
. Crucial tyrosines are buried in the membrane and are largely protected from phosphorylation in resting T cells. It is not clear how CD3
CD
dissociates from the membrane in antigen-stimulated T cells. The antigen engagement of even a single TCR triggers a Ca
2+
influx
11
and TCR-proximal Ca
2+
concentration is higher than the average cytosolic Ca
2+
concentration
12
. Our biochemical, live-cell fluorescence resonance energy transfer and NMR experiments showed that an increase in Ca
2+
concentration induced the dissociation of CD3
CD
from the membrane and the solvent exposure of tyrosine residues. As a consequence, CD3 tyrosine phosphorylation was significantly enhanced by Ca
2+
influx. Moreover, when compared with wild-type cells, Ca
2+
channel-deficient T cells had substantially lower levels of CD3 phosphorylation after stimulation. The effect of Ca
2+
on facilitating CD3 phosphorylation is primarily due to the charge of this ion, as demonstrated by the fact that replacing Ca
2+
with the non-physiological ion Sr
2+
resulted in the same feedback effect. Finally,
31
P NMR spectroscopy showed that Ca
2+
bound |
| doi_str_mv | 10.1038/nature11699 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmed_cross</sourceid><recordid>TN_cdi_crossref_primary_10_1038_nature11699</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>23201688</sourcerecordid><originalsourceid>FETCH-LOGICAL-c286t-5d94e281d2b03c0a7f197d0959543310d9cedf77c9d5ed92c575ea509b4b25dd3</originalsourceid><addsrcrecordid>eNpt0DtPwzAQB3ALgaAUJnbkhakEbCd-jajiJVViaefIsS9pqjSJbAep355ULY-B6aS7n-50f4RuKHmgJFWPrYmDB0qF1idoQjMpkkwoeYomhDCVEJWKC3QZwoYQwqnMztEFSxmhQqkJWs0Nm2EP1dCYCAEvEwtNMzYs9LHz2NhYf5pYdy0udnjbub2r2wrHNWC7Nr4C3PuuBx93uCtxU_e1C1forDRNgOtjnaLVy_Ny_pYsPl7f50-LxDIlYsKdzoAp6lhBUkuMLKmWjmiueZamlDhtwZVSWu04OM0slxwMJ7rICsadS6dodthrfReChzLvfb01fpdTku_Dyf-EM-rbg-6HYgvux36nMYK7IzDBmqb0prV1-HVCcsG1HN39wYVx1Fbg8003-Hb89N-7X_3ofVk</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Ca2+ regulates T-cell receptor activation by modulating the charge property of lipids</title><source>MEDLINE</source><source>Nature</source><source>Alma/SFX Local Collection</source><creator>Shi, Xiaoshan ; Bi, Yunchen ; Yang, Wei ; Guo, Xingdong ; Jiang, Yan ; Wan, Chanjuan ; Li, Lunyi ; Bai, Yibing ; Guo, Jun ; Wang, Yujuan ; Chen, Xiangjun ; Wu, Bo ; Sun, Hongbin ; Liu, Wanli ; Wang, Junfeng ; Xu, Chenqi</creator><creatorcontrib>Shi, Xiaoshan ; Bi, Yunchen ; Yang, Wei ; Guo, Xingdong ; Jiang, Yan ; Wan, Chanjuan ; Li, Lunyi ; Bai, Yibing ; Guo, Jun ; Wang, Yujuan ; Chen, Xiangjun ; Wu, Bo ; Sun, Hongbin ; Liu, Wanli ; Wang, Junfeng ; Xu, Chenqi</creatorcontrib><description>Calcium–lipid electrostatic interactions are shown to amplify the tyrosine phosphorylation of CD3ε and CD3ζ in T-cell antigen receptor complex.
Calcium control of T cells
These authors show that Ca
2+
can regulate the ionic interaction between the T-cell receptor–CD3 complex (TCR) and anionic phospholipids — important components in adaptive immunity — by modulating the electrostatic property of phospholipids. Ca
2+
is shown to bind to the phosphate group in anionic phospholipid headgroups and undermines CD3
CD
–membrane ionic interaction, thus facilitating TCR phosphorylation. This positive feedback regulation by Ca
2+
can amplify TCR signalling to potentiate the effector function of T cells against invading pathogens.
Ionic protein–lipid interactions are critical for the structure and function of membrane receptors, ion channels, integrins and many other proteins
1
,
2
,
3
,
4
,
5
,
6
,
7
. However, the regulatory mechanism of these interactions is largely unknown. Here we show that Ca
2+
can bind directly to anionic phospholipids and thus modulate membrane protein function. The activation of T-cell antigen receptor–CD3 complex (TCR), a key membrane receptor for adaptive immunity, is regulated by ionic interactions between positively charged CD3ε/ζ cytoplasmic domains (CD3
CD
) and negatively charged phospholipids in the plasma membrane
1
,
8
,
9
,
10
. Crucial tyrosines are buried in the membrane and are largely protected from phosphorylation in resting T cells. It is not clear how CD3
CD
dissociates from the membrane in antigen-stimulated T cells. The antigen engagement of even a single TCR triggers a Ca
2+
influx
11
and TCR-proximal Ca
2+
concentration is higher than the average cytosolic Ca
2+
concentration
12
. Our biochemical, live-cell fluorescence resonance energy transfer and NMR experiments showed that an increase in Ca
2+
concentration induced the dissociation of CD3
CD
from the membrane and the solvent exposure of tyrosine residues. As a consequence, CD3 tyrosine phosphorylation was significantly enhanced by Ca
2+
influx. Moreover, when compared with wild-type cells, Ca
2+
channel-deficient T cells had substantially lower levels of CD3 phosphorylation after stimulation. The effect of Ca
2+
on facilitating CD3 phosphorylation is primarily due to the charge of this ion, as demonstrated by the fact that replacing Ca
2+
with the non-physiological ion Sr
2+
resulted in the same feedback effect. Finally,
31
P NMR spectroscopy showed that Ca
2+
bound to the phosphate group in anionic phospholipids at physiological concentrations, thus neutralizing the negative charge of phospholipids. Rather than initiating CD3 phosphorylation, this regulatory pathway of Ca
2+
has a positive feedback effect on amplifying and sustaining CD3 phosphorylation and should enhance T-cell sensitivity to foreign antigens. Our study thus provides a new regulatory mechanism of Ca
2+
to T-cell activation involving direct lipid manipulation.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/nature11699</identifier><identifier>PMID: 23201688</identifier><identifier>CODEN: NATUAS</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/250/1619/554/1775 ; 631/45/287 ; 631/80/86/1999 ; Animals ; Biological and medical sciences ; Calcium - metabolism ; Calcium - pharmacology ; Cell Membrane - metabolism ; Cytoplasm - metabolism ; Feedback, Physiological - drug effects ; Fundamental and applied biological sciences. Psychology ; Fundamental immunology ; Humanities and Social Sciences ; Humans ; Immunobiology ; Jurkat Cells ; letter ; Lipid Bilayers - chemistry ; Lipid Bilayers - metabolism ; Lymphocyte Activation - drug effects ; Lymphoid cells: ontogeny, maturation, markers, receptors, circulation and recirculation ; Mice ; multidisciplinary ; Phospholipids - chemistry ; Phospholipids - metabolism ; Phosphorylation - drug effects ; Receptor-CD3 Complex, Antigen, T-Cell - drug effects ; Receptor-CD3 Complex, Antigen, T-Cell - immunology ; Receptor-CD3 Complex, Antigen, T-Cell - metabolism ; Science ; Signal Transduction - drug effects ; Solvents - chemistry ; Solvents - metabolism ; Static Electricity ; T-Lymphocytes - drug effects ; T-Lymphocytes - immunology ; T-Lymphocytes - metabolism ; Tyrosine - metabolism</subject><ispartof>Nature (London), 2013-01, Vol.493 (7430), p.111-115</ispartof><rights>Springer Nature Limited 2012</rights><rights>2014 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c286t-5d94e281d2b03c0a7f197d0959543310d9cedf77c9d5ed92c575ea509b4b25dd3</citedby><cites>FETCH-LOGICAL-c286t-5d94e281d2b03c0a7f197d0959543310d9cedf77c9d5ed92c575ea509b4b25dd3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,27928,27929</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26756597$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23201688$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shi, Xiaoshan</creatorcontrib><creatorcontrib>Bi, Yunchen</creatorcontrib><creatorcontrib>Yang, Wei</creatorcontrib><creatorcontrib>Guo, Xingdong</creatorcontrib><creatorcontrib>Jiang, Yan</creatorcontrib><creatorcontrib>Wan, Chanjuan</creatorcontrib><creatorcontrib>Li, Lunyi</creatorcontrib><creatorcontrib>Bai, Yibing</creatorcontrib><creatorcontrib>Guo, Jun</creatorcontrib><creatorcontrib>Wang, Yujuan</creatorcontrib><creatorcontrib>Chen, Xiangjun</creatorcontrib><creatorcontrib>Wu, Bo</creatorcontrib><creatorcontrib>Sun, Hongbin</creatorcontrib><creatorcontrib>Liu, Wanli</creatorcontrib><creatorcontrib>Wang, Junfeng</creatorcontrib><creatorcontrib>Xu, Chenqi</creatorcontrib><title>Ca2+ regulates T-cell receptor activation by modulating the charge property of lipids</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>Calcium–lipid electrostatic interactions are shown to amplify the tyrosine phosphorylation of CD3ε and CD3ζ in T-cell antigen receptor complex.
Calcium control of T cells
These authors show that Ca
2+
can regulate the ionic interaction between the T-cell receptor–CD3 complex (TCR) and anionic phospholipids — important components in adaptive immunity — by modulating the electrostatic property of phospholipids. Ca
2+
is shown to bind to the phosphate group in anionic phospholipid headgroups and undermines CD3
CD
–membrane ionic interaction, thus facilitating TCR phosphorylation. This positive feedback regulation by Ca
2+
can amplify TCR signalling to potentiate the effector function of T cells against invading pathogens.
Ionic protein–lipid interactions are critical for the structure and function of membrane receptors, ion channels, integrins and many other proteins
1
,
2
,
3
,
4
,
5
,
6
,
7
. However, the regulatory mechanism of these interactions is largely unknown. Here we show that Ca
2+
can bind directly to anionic phospholipids and thus modulate membrane protein function. The activation of T-cell antigen receptor–CD3 complex (TCR), a key membrane receptor for adaptive immunity, is regulated by ionic interactions between positively charged CD3ε/ζ cytoplasmic domains (CD3
CD
) and negatively charged phospholipids in the plasma membrane
1
,
8
,
9
,
10
. Crucial tyrosines are buried in the membrane and are largely protected from phosphorylation in resting T cells. It is not clear how CD3
CD
dissociates from the membrane in antigen-stimulated T cells. The antigen engagement of even a single TCR triggers a Ca
2+
influx
11
and TCR-proximal Ca
2+
concentration is higher than the average cytosolic Ca
2+
concentration
12
. Our biochemical, live-cell fluorescence resonance energy transfer and NMR experiments showed that an increase in Ca
2+
concentration induced the dissociation of CD3
CD
from the membrane and the solvent exposure of tyrosine residues. As a consequence, CD3 tyrosine phosphorylation was significantly enhanced by Ca
2+
influx. Moreover, when compared with wild-type cells, Ca
2+
channel-deficient T cells had substantially lower levels of CD3 phosphorylation after stimulation. The effect of Ca
2+
on facilitating CD3 phosphorylation is primarily due to the charge of this ion, as demonstrated by the fact that replacing Ca
2+
with the non-physiological ion Sr
2+
resulted in the same feedback effect. Finally,
31
P NMR spectroscopy showed that Ca
2+
bound to the phosphate group in anionic phospholipids at physiological concentrations, thus neutralizing the negative charge of phospholipids. Rather than initiating CD3 phosphorylation, this regulatory pathway of Ca
2+
has a positive feedback effect on amplifying and sustaining CD3 phosphorylation and should enhance T-cell sensitivity to foreign antigens. Our study thus provides a new regulatory mechanism of Ca
2+
to T-cell activation involving direct lipid manipulation.</description><subject>631/250/1619/554/1775</subject><subject>631/45/287</subject><subject>631/80/86/1999</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Calcium - metabolism</subject><subject>Calcium - pharmacology</subject><subject>Cell Membrane - metabolism</subject><subject>Cytoplasm - metabolism</subject><subject>Feedback, Physiological - drug effects</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Fundamental immunology</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Immunobiology</subject><subject>Jurkat Cells</subject><subject>letter</subject><subject>Lipid Bilayers - chemistry</subject><subject>Lipid Bilayers - metabolism</subject><subject>Lymphocyte Activation - drug effects</subject><subject>Lymphoid cells: ontogeny, maturation, markers, receptors, circulation and recirculation</subject><subject>Mice</subject><subject>multidisciplinary</subject><subject>Phospholipids - chemistry</subject><subject>Phospholipids - metabolism</subject><subject>Phosphorylation - drug effects</subject><subject>Receptor-CD3 Complex, Antigen, T-Cell - drug effects</subject><subject>Receptor-CD3 Complex, Antigen, T-Cell - immunology</subject><subject>Receptor-CD3 Complex, Antigen, T-Cell - metabolism</subject><subject>Science</subject><subject>Signal Transduction - drug effects</subject><subject>Solvents - chemistry</subject><subject>Solvents - metabolism</subject><subject>Static Electricity</subject><subject>T-Lymphocytes - drug effects</subject><subject>T-Lymphocytes - immunology</subject><subject>T-Lymphocytes - metabolism</subject><subject>Tyrosine - metabolism</subject><issn>0028-0836</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0DtPwzAQB3ALgaAUJnbkhakEbCd-jajiJVViaefIsS9pqjSJbAep355ULY-B6aS7n-50f4RuKHmgJFWPrYmDB0qF1idoQjMpkkwoeYomhDCVEJWKC3QZwoYQwqnMztEFSxmhQqkJWs0Nm2EP1dCYCAEvEwtNMzYs9LHz2NhYf5pYdy0udnjbub2r2wrHNWC7Nr4C3PuuBx93uCtxU_e1C1forDRNgOtjnaLVy_Ny_pYsPl7f50-LxDIlYsKdzoAp6lhBUkuMLKmWjmiueZamlDhtwZVSWu04OM0slxwMJ7rICsadS6dodthrfReChzLvfb01fpdTku_Dyf-EM-rbg-6HYgvux36nMYK7IzDBmqb0prV1-HVCcsG1HN39wYVx1Fbg8003-Hb89N-7X_3ofVk</recordid><startdate>20130103</startdate><enddate>20130103</enddate><creator>Shi, Xiaoshan</creator><creator>Bi, Yunchen</creator><creator>Yang, Wei</creator><creator>Guo, Xingdong</creator><creator>Jiang, Yan</creator><creator>Wan, Chanjuan</creator><creator>Li, Lunyi</creator><creator>Bai, Yibing</creator><creator>Guo, Jun</creator><creator>Wang, Yujuan</creator><creator>Chen, Xiangjun</creator><creator>Wu, Bo</creator><creator>Sun, Hongbin</creator><creator>Liu, Wanli</creator><creator>Wang, Junfeng</creator><creator>Xu, Chenqi</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20130103</creationdate><title>Ca2+ regulates T-cell receptor activation by modulating the charge property of lipids</title><author>Shi, Xiaoshan ; Bi, Yunchen ; Yang, Wei ; Guo, Xingdong ; Jiang, Yan ; Wan, Chanjuan ; Li, Lunyi ; Bai, Yibing ; Guo, Jun ; Wang, Yujuan ; Chen, Xiangjun ; Wu, Bo ; Sun, Hongbin ; Liu, Wanli ; Wang, Junfeng ; Xu, Chenqi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c286t-5d94e281d2b03c0a7f197d0959543310d9cedf77c9d5ed92c575ea509b4b25dd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>631/250/1619/554/1775</topic><topic>631/45/287</topic><topic>631/80/86/1999</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Calcium - metabolism</topic><topic>Calcium - pharmacology</topic><topic>Cell Membrane - metabolism</topic><topic>Cytoplasm - metabolism</topic><topic>Feedback, Physiological - drug effects</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Fundamental immunology</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Immunobiology</topic><topic>Jurkat Cells</topic><topic>letter</topic><topic>Lipid Bilayers - chemistry</topic><topic>Lipid Bilayers - metabolism</topic><topic>Lymphocyte Activation - drug effects</topic><topic>Lymphoid cells: ontogeny, maturation, markers, receptors, circulation and recirculation</topic><topic>Mice</topic><topic>multidisciplinary</topic><topic>Phospholipids - chemistry</topic><topic>Phospholipids - metabolism</topic><topic>Phosphorylation - drug effects</topic><topic>Receptor-CD3 Complex, Antigen, T-Cell - drug effects</topic><topic>Receptor-CD3 Complex, Antigen, T-Cell - immunology</topic><topic>Receptor-CD3 Complex, Antigen, T-Cell - metabolism</topic><topic>Science</topic><topic>Signal Transduction - drug effects</topic><topic>Solvents - chemistry</topic><topic>Solvents - metabolism</topic><topic>Static Electricity</topic><topic>T-Lymphocytes - drug effects</topic><topic>T-Lymphocytes - immunology</topic><topic>T-Lymphocytes - metabolism</topic><topic>Tyrosine - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shi, Xiaoshan</creatorcontrib><creatorcontrib>Bi, Yunchen</creatorcontrib><creatorcontrib>Yang, Wei</creatorcontrib><creatorcontrib>Guo, Xingdong</creatorcontrib><creatorcontrib>Jiang, Yan</creatorcontrib><creatorcontrib>Wan, Chanjuan</creatorcontrib><creatorcontrib>Li, Lunyi</creatorcontrib><creatorcontrib>Bai, Yibing</creatorcontrib><creatorcontrib>Guo, Jun</creatorcontrib><creatorcontrib>Wang, Yujuan</creatorcontrib><creatorcontrib>Chen, Xiangjun</creatorcontrib><creatorcontrib>Wu, Bo</creatorcontrib><creatorcontrib>Sun, Hongbin</creatorcontrib><creatorcontrib>Liu, Wanli</creatorcontrib><creatorcontrib>Wang, Junfeng</creatorcontrib><creatorcontrib>Xu, Chenqi</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shi, Xiaoshan</au><au>Bi, Yunchen</au><au>Yang, Wei</au><au>Guo, Xingdong</au><au>Jiang, Yan</au><au>Wan, Chanjuan</au><au>Li, Lunyi</au><au>Bai, Yibing</au><au>Guo, Jun</au><au>Wang, Yujuan</au><au>Chen, Xiangjun</au><au>Wu, Bo</au><au>Sun, Hongbin</au><au>Liu, Wanli</au><au>Wang, Junfeng</au><au>Xu, Chenqi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ca2+ regulates T-cell receptor activation by modulating the charge property of lipids</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2013-01-03</date><risdate>2013</risdate><volume>493</volume><issue>7430</issue><spage>111</spage><epage>115</epage><pages>111-115</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><coden>NATUAS</coden><abstract>Calcium–lipid electrostatic interactions are shown to amplify the tyrosine phosphorylation of CD3ε and CD3ζ in T-cell antigen receptor complex.
Calcium control of T cells
These authors show that Ca
2+
can regulate the ionic interaction between the T-cell receptor–CD3 complex (TCR) and anionic phospholipids — important components in adaptive immunity — by modulating the electrostatic property of phospholipids. Ca
2+
is shown to bind to the phosphate group in anionic phospholipid headgroups and undermines CD3
CD
–membrane ionic interaction, thus facilitating TCR phosphorylation. This positive feedback regulation by Ca
2+
can amplify TCR signalling to potentiate the effector function of T cells against invading pathogens.
Ionic protein–lipid interactions are critical for the structure and function of membrane receptors, ion channels, integrins and many other proteins
1
,
2
,
3
,
4
,
5
,
6
,
7
. However, the regulatory mechanism of these interactions is largely unknown. Here we show that Ca
2+
can bind directly to anionic phospholipids and thus modulate membrane protein function. The activation of T-cell antigen receptor–CD3 complex (TCR), a key membrane receptor for adaptive immunity, is regulated by ionic interactions between positively charged CD3ε/ζ cytoplasmic domains (CD3
CD
) and negatively charged phospholipids in the plasma membrane
1
,
8
,
9
,
10
. Crucial tyrosines are buried in the membrane and are largely protected from phosphorylation in resting T cells. It is not clear how CD3
CD
dissociates from the membrane in antigen-stimulated T cells. The antigen engagement of even a single TCR triggers a Ca
2+
influx
11
and TCR-proximal Ca
2+
concentration is higher than the average cytosolic Ca
2+
concentration
12
. Our biochemical, live-cell fluorescence resonance energy transfer and NMR experiments showed that an increase in Ca
2+
concentration induced the dissociation of CD3
CD
from the membrane and the solvent exposure of tyrosine residues. As a consequence, CD3 tyrosine phosphorylation was significantly enhanced by Ca
2+
influx. Moreover, when compared with wild-type cells, Ca
2+
channel-deficient T cells had substantially lower levels of CD3 phosphorylation after stimulation. The effect of Ca
2+
on facilitating CD3 phosphorylation is primarily due to the charge of this ion, as demonstrated by the fact that replacing Ca
2+
with the non-physiological ion Sr
2+
resulted in the same feedback effect. Finally,
31
P NMR spectroscopy showed that Ca
2+
bound to the phosphate group in anionic phospholipids at physiological concentrations, thus neutralizing the negative charge of phospholipids. Rather than initiating CD3 phosphorylation, this regulatory pathway of Ca
2+
has a positive feedback effect on amplifying and sustaining CD3 phosphorylation and should enhance T-cell sensitivity to foreign antigens. Our study thus provides a new regulatory mechanism of Ca
2+
to T-cell activation involving direct lipid manipulation.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>23201688</pmid><doi>10.1038/nature11699</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2013-01, Vol.493 (7430), p.111-115 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_crossref_primary_10_1038_nature11699 |
| source | MEDLINE; Nature; Alma/SFX Local Collection |
| subjects | 631/250/1619/554/1775 631/45/287 631/80/86/1999 Animals Biological and medical sciences Calcium - metabolism Calcium - pharmacology Cell Membrane - metabolism Cytoplasm - metabolism Feedback, Physiological - drug effects Fundamental and applied biological sciences. Psychology Fundamental immunology Humanities and Social Sciences Humans Immunobiology Jurkat Cells letter Lipid Bilayers - chemistry Lipid Bilayers - metabolism Lymphocyte Activation - drug effects Lymphoid cells: ontogeny, maturation, markers, receptors, circulation and recirculation Mice multidisciplinary Phospholipids - chemistry Phospholipids - metabolism Phosphorylation - drug effects Receptor-CD3 Complex, Antigen, T-Cell - drug effects Receptor-CD3 Complex, Antigen, T-Cell - immunology Receptor-CD3 Complex, Antigen, T-Cell - metabolism Science Signal Transduction - drug effects Solvents - chemistry Solvents - metabolism Static Electricity T-Lymphocytes - drug effects T-Lymphocytes - immunology T-Lymphocytes - metabolism Tyrosine - metabolism |
| title | Ca2+ regulates T-cell receptor activation by modulating the charge property of lipids |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-17T04%3A18%3A57IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-pubmed_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Ca2+%20regulates%20T-cell%20receptor%20activation%20by%20modulating%20the%20charge%20property%20of%20lipids&rft.jtitle=Nature%20(London)&rft.au=Shi,%20Xiaoshan&rft.date=2013-01-03&rft.volume=493&rft.issue=7430&rft.spage=111&rft.epage=115&rft.pages=111-115&rft.issn=0028-0836&rft.eissn=1476-4687&rft.coden=NATUAS&rft_id=info:doi/10.1038/nature11699&rft_dat=%3Cpubmed_cross%3E23201688%3C/pubmed_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/23201688&rfr_iscdi=true |