Glycolipid antigen induces long-term natural killer T cell anergy in mice.
Natural killer T (NKT) cells recognize glycolipid antigens presented by the MHC class I-related glycoprotein CD1d. The in vivo dynamics of the NKT cell population in response to glycolipid activation remain poorly understood. Here, we show that a single administration of the synthetic glycolipid alpha-galactosylceramide (alpha-GalCer) induces long-term NKT cell unresponsiveness in mice. NKT cells failed to proliferate and produce IFN-gamma upon alpha-GalCer restimulation but retained the capacity to produce IL-4. Consequently, we found that activation of anergic NKT cells with alpha-GalCer exacerbated, rather than prevented, B16 metastasis formation, but that these cells retained their capacity to protect mice against experimental autoimmune encephalomyelitis. NKT cell anergy was induced in a thymus-independent manner and maintained in an NKT cell-autonomous manner. The anergic state could be broken by IL-2 and by stimuli that bypass proximal TCR signaling events. Collectively, the kinetics of initial NKT cell activation, expansion, and induction of anergy in response to alpha-GalCer administration resemble the responses of conventional T cells to strong stimuli such as superantigens. Our findings have important implications for the development of NKT cell-based vaccines and immunotherapies.
Parekh
Vrajesh V
VV
Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Wilson
Michael T
MT
Olivares-Villagómez
Danyvid
D
Singh
Avneesh K
AK
Wu
Lan
L
Wang
Chyung-Ru
CR
Joyce
Sebastian
S
Van Kaer
Luc
L
D000818:Animals; D017635:Clonal Anergy; D005260:Female; D005699:Galactosylceramides / Q000008:administration & dosage / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology; D015847:Interleukin-4 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008099:Liver / Q000166:cytology; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013154:Spleen / Q000166:cytology
D005699:Galactosylceramides; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D015847:Interleukin-4; D007371:Interferon-gamma