Nanoscale increases in CD2-CD48-mediated intermembrane spacing decrease adhesion and reorganize the immunological synapse.
The relationship between intermembrane spacing, adhesion efficiency, and lateral organization of adhesion receptors has not been established for any adhesion system. We have utilized the CD2 ligand CD48 with two (wild type CD48 (CD48-WT)), four (CD48-CD2), or five (CD48-CD22) Ig-like domains. CD48-WT was 10-fold more efficient in mediating adhesion than CD48-CD2 or CD48-CD22. Electron tomography of contact areas with planar bilayers demonstrated average intermembrane spacing of 12.8 nm with CD48-WT, 14.7 nm with CD48-CD2, and 15.6 nm with CD48-CD22. Both CD48-CD2 and CD48-CD22 chimeras segregated completely from CD48-WT in mixed contact areas. In contrast, CD48-CD2 and CD48-CD22 co-localized when mixed contacts were formed. Confocal imaging of immunological synapses formed between primary T lymphocytes and Chinese hamster ovary cells presenting major histocompatibility complex-peptide complexes, and different forms of CD48 demonstrated that CD48-CD2 and CD48-CD22 induce an eccentric CD2/T cell antigen receptor cluster. We propose that this reorganization of the immunological synapse sequesters the T cell antigen receptor in a location where it cannot interact with its ligand and dramatically reduces T cell sensitivity.
Milstein
Oren
O
Programs in Molecular Pathogenesis and Structural Biology, Helen and Martin Kimmel Center for Biology and Medicine of the Skirball Institute and New York University School of Medicine, New York, New York 10016, USA.
Tseng
Su-Yi
SY
Starr
Toby
T
Llodra
Jaime
J
Nans
Andrea
A
Liu
Mengling
M
Wild
Martin K
MK
van der Merwe
P Anton
PA
Stokes
David L
DL
Reisner
Yair
Y
Dustin
Michael L
ML
D000818:Animals; D015703:Antigens, CD / Q000737:chemistry*; D018801:CD2 Antigens / Q000737:chemistry*; D000071178:CD48 Antigen; D016466:CHO Cells; D002448:Cell Adhesion; D049109:Cell Proliferation; D006224:Cricetinae; D003412:Cricetulus; D055032:Electron Microscope Tomography / Q000379:methods; D005434:Flow Cytometry; D054992:Immunological Synapses / Q000502:physiology*; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000737:chemistry; D013601:T-Lymphocytes / Q000378:metabolism*
D015703:Antigens, CD; D018801:CD2 Antigens; D000071178:CD48 Antigen; C000604066:Cd48 protein, mouse; D051918:Sialic Acid Binding Ig-like Lectin 2