Dynamic reorganization of chemokine receptors, cholesterol, lipid rafts, and adhesion molecules to sites of CD4 engagement.
T cell polarization and redistribution of cellular components are critical to processes such as activation, migration, and potentially HIV infection. Here, we investigate the effects of CD4 engagement on the redistribution and localization of chemokine receptors, CXCR4 and CCR5, adhesion molecules, and lipid raft components including cholesterol, GM1, and glycosyl-phosphatidylinositol (GPI)-anchored proteins. We demonstrate that anti-CD4-coated beads (alpha CD4-B) rapidly induce co-capping of chemokine receptors as well as GPI-anchored proteins and adhesion molecules with membrane cholesterol and lipid rafts on human T cell lines and primary T cells to the area of bead-cell contact. This process was dependent on the presence of cellular cholesterol, cytoskeletal reorganization, and lck signaling. Lck-deficient JCaM 1.6 cells failed to cap CXCR4 or lipid rafts to alpha CD4-B. Biochemical analysis reveals that CXCR4 and LFA-1 are recruited to lipid rafts upon CD4 but not CD45 engagement. Furthermore, we also demonstrate T cell capping of both lipid rafts and chemokine receptors at sites of contact with HIV-infected cells, despite the binding of an HIV inhibitory mAb to CXCR4. We conclude that cell surface rearrangements in response to CD4 engagement may serve as a means to enhance cell-to-cell signaling at the immunological synapse and modulate chemokine responsiveness, as well as facilitate HIV entry and expansion by synaptic transmission.
Nguyen
Dzung H
DH
Laboratory of Immunology, National Institute on Aging, Intramural Research Program, NIH, DHHS, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
Giri
Banabihari
B
Collins
Gary
G
Taub
Dennis D
DD
D015704:CD4 Antigens / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002449:Cell Aggregation / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D016764:Cell Polarity / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism*; D005677:G(M1) Ganglioside / Q000378:metabolism; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000502:physiology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*
D015704:CD4 Antigens; D015815:Cell Adhesion Molecules; D017261:Glycosylphosphatidylinositols; D016169:Lymphocyte Function-Associated Antigen-1; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D005677:G(M1) Ganglioside; D002784:Cholesterol; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)