Immobilization of glycosylphosphatidylinositol-anchored proteins inhibits T cell growth but not function.
Accumulating evidence suggests that proteins tethered to the plasma membrane through glycosylphosphatidylinositol (GPI) anchors share common biological properties. In the present study we demonstrate that GPI-anchored proteins regulate T cell growth. Specifically, anti-TCR-induced proliferation was profoundly inhibited by co-immobilized mAb specific for Thy-1, CD48 and Ly6A/E. However, neither IL-2 production nor the effector function of cytotoxic T lymphocytes was impaired in these circumstances. Analysis of the IL-2 receptor (IL-2R) signaling pathway revealed that the association of IL-2R beta and gamma chains with the Janus kinases, JAK1 and JAK3, was not perturbed in the presence of mAb specific for GPI-linked proteins. However, in these conditions, IL-2-mediated recruitment of IL-2Ralpha, beta and gamma chains, resulting in the formation of the high-affinity hetero-trimeric IL-2R, was inhibited. The resulting phosphorylation of JAK1 and JAK3, indicative of their activation states, was correspondingly reduced. These results characterize a novel state of T cell physiology in which effector function is maintained, in the absence of clonal expansion. A physiological role for GPI-anchored proteins in the maintenance of cellular homeostasis and function is discussed.
Marmor
M D
MD
Department of Immunology, University of Toronto, and The Arthritis and Immune Disorder Research Centre, The Toronto Hospital, Toronto, Ontario M5G 2M9, Canada.
Bachmann
M F
MF
Ohashi
P S
PS
Malek
T R
TR
Julius
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000918:Antibody Specificity; D015703:Antigens, CD / Q000276:immunology; D000950:Antigens, Ly / Q000276:immunology; D000071178:CD48 Antigen; D002352:Carrier Proteins / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D017261:Glycosylphosphatidylinositols / Q000037:antagonists & inhibitors / Q000502:physiology*; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D008213:Lymphocyte Activation / Q000502:physiology*; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology; D018800:Thy-1 Antigens / Q000276:immunology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000950:Antigens, Ly; D000071178:CD48 Antigen; D002352:Carrier Proteins; C000604066:Cd48 protein, mouse; D017261:Glycosylphosphatidylinositols; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D018800:Thy-1 Antigens; D011505:Protein-Tyrosine Kinases; C507905:Jak1 protein, mouse; C507935:Jak3 protein, mouse; D053613:Janus Kinase 1; D053616:Janus Kinase 3