Cutting edge: CD28 engagement releases antigen-activated invariant NKT cells from the inhibitory effects of PD-1.
Costimulatory and coinhibitory signals are important for the maintenance of immune homeostasis both in the steady state and during immune responses. In this study, we explore the relative contributions of these signals to the rapid production of large amounts of cytokines by activated invariant NKT cells (iNKT cells). We find that upon antigenic stimulation, iNKT cells rapidly up-regulate programmed death (PD)-1 and induce high levels of PD ligand 1 and costimulatory molecules on the surface of cognate Ag-presenting dendritic cells and that iNKT cells require a CD28 signal to secrete cytokines in the presence of a PD-1/PD ligand 1 interaction. CD28-deficient iNKT cells synthesized but failed to secrete cytokines during activation, and blockade of the PD-1 pathway restored the ability of CD28-deficient iNKT cells to secrete cytokines. The opposing functions of CD28 and PD-1 thus tightly regulate the unique effector function iNKT cells.
Wang
Jianxiong
J
Department of Biochemistry and Molecular Biology, Julia McFarlane Diabetes Research Centre, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
Cheng
Lu
L
Wondimu
Zenebech
Z
Swain
Mark
M
Santamaria
Pere
P
Yang
Yang
Y
D000818:Animals; D000938:Antigen-Presenting Cells; D000943:Antigens, Differentiation / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D006706:Homeostasis / Q000276:immunology*; D007107:Immune System / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D055611:Natural Killer T-Cells / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic / Q000276:immunology; D015854:Up-Regulation
D000943:Antigens, Differentiation; D018106:CD28 Antigens; D016207:Cytokines; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic