Sep 26: Regulation of T cell activation by acidic phospholipids

Speaker：Chenqi Xu，Professor, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences

Host: Prof. Yuping Lai

When: 2013-9-26  13:30

Where: Conference Room 534, School of Life Sciences

Abstract: Plasma member is an asymmetrical lipid bilayer environment and its inner-leaflet is enriched of acidic phospholipids. The negatively charged acidic phospholipids interact with positively charged proteins and thus regulate critical signaling events. We are studying how the ionic protein-lipid interaction regulates the activation of T-cell receptor (TCR), a key immunoreceptor that recognizes antigen and initiates the adaptive immune responses against invading pathogens. TCR is composed of four subunits: the antigen recognition subunit TCR and signaling subunits CD3, and Antigen binding on the TCR subunit generates mechanical force and this physical signal can be transduced across the membrane and decoded to CD3 tyrosine phosphorylation signal. The molecular mechanism of this physical-to-chemical signal transduction process remains elusive. The cytoplasmic domains of CD3 and chains (CD3_CD and CD3_CD) are enriched of basic residues and we and other groups find that CD3_CD and CD3_CD interact with the acidic phospholipids in the plasma membrane. The key tyrosine residues in CD3_CD and CD3_CD are fully embedded in the hydrophobic core of the membrane bilayer, which prevents the spontaneous phosphorylation of CD3 chains in quiescent T cells. After T cells are stimulated by antigens, Ca²⁺ ions locally influx into T cells and generate Ca²⁺ microdomains proximal to TCRs. We find that Ca²⁺ ions can directly bind to the acidic phospholipids and neutralize their negative charges, which in turn disrupts the ionic CD3-lipid interaction and lead to the solvent exposure of the key tyrosine residues. Ca²⁺ can thus help CD3 phosphorylation and amplify the weak antigen-stimulating signal to fully activate T cells. These studies demonstrate that membrane lipids can sequester TCR activation sites at quiescent stage, whereas Ca²⁺ can release these activation sites for phosphorylation in antigen-stimulated T cells. We find that this tyrosine sequestration-release mechanism is also applicable to other immunoreceptors.