A fundamental bimodal role for neuropeptide Y1 receptor in the immune system.
Psychological conditions, including stress, compromise immune defenses. Although this concept is not novel, the molecular mechanism behind it remains unclear. Neuropeptide Y (NPY) in the central nervous system is a major regulator of numerous physiological functions, including stress. Postganglionic sympathetic nerves innervating lymphoid organs release NPY, which together with other peptides activate five Y receptors (Y1, Y2, Y4, Y5, and y(6)). Using Y1-deficient (Y1(-/-)) mice, we showed that Y1(-/-) T cells are hyperresponsive to activation and trigger severe colitis after transfer into lymphopenic mice. Thus, signaling through Y1 receptor on T cells inhibits T cell activation and controls the magnitude of T cell responses. Paradoxically, Y1(-/-) mice were resistant to T helper type 1 (Th1) cell-mediated inflammatory responses and showed reduced levels of the Th1 cell-promoting cytokine interleukin 12 and reduced interferon gamma production. This defect was due to functionally impaired antigen-presenting cells (APCs), and consequently, Y1(-/-) mice had reduced numbers of effector T cells. These results demonstrate a fundamental bimodal role for the Y1 receptor in the immune system, serving as a strong negative regulator on T cells as well as a key activator of APC function. Our findings uncover a sophisticated molecular mechanism regulating immune cell functions that can lead to stress-induced immunosuppression.
Wheway
Julie
J
The Arthritis and Inflammation Research Program, The Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
Mackay
Charles R
CR
Newton
Rebecca A
RA
Sainsbury
Amanda
A
Boey
Dana
D
Herzog
Herbert
H
Mackay
Fabienne
F
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D001327:Autoimmune Diseases / Q000097:blood / Q000235:genetics / Q000276:immunology; D003092:Colitis / Q000097:blood / Q000235:genetics / Q000276:immunology; D005260:Female; D007249:Inflammation / Q000097:blood / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D018655:Lymphocyte Count; D008221:Lymphoid Tissue / Q000276:immunology / Q000294:innervation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009478:Neuropeptide Y / Q000276:immunology*; D017476:Receptors, Neuropeptide Y / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013315:Stress, Psychological / Q000097:blood / Q000235:genetics / Q000276:immunology*; D017779:Sympathetic Fibers, Postganglionic / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000637:transplantation
D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor; D018664:Interleukin-12; D007371:Interferon-gamma