Development of spontaneous anergy in invariant natural killer T cells in a mouse model of dyslipidemia.
OBJECTIVE
In this study, we investigated whether dyslipidemia-associated perturbed invariant natural killer T (iNKT) cell function is due to intrinsic changes in iNKT cells or defects in the ability of antigen-presenting cells to activate iNKT cells.


RESULTS
We compared iNKT cell expansion and cytokine production in C57BL/6J (B6) and apolipoprotein E-deficient (apoE(-/-)) mice. In response to in vivo stimulation with alpha-galactosylceramide, a prototypic iNKT cell glycolipid antigen, apoE(-/-) mice showed significantly decreased splenic iNKT cell expansion at 3 days after injection, a profile associated with iNKT cell anergy due to chronic stimulation. This decrease in expansion and cytokine production was accompanied by a 2-fold increase in percentage of iNKT cells expressing the inhibitory marker programmed death-1 in apoE(-/-) mice compared with controls. However, in vivo and in vitro blockade of programmed death-1 using monoclonal antibody was not able to restore functions of iNKT cells from apoE(-/-) mice to B6 levels. iNKT cells from apoE(-/-) mice also had increased intracellular T cell receptor and Ly49 expression, a phenotype associated with previous activation. Changes in iNKT cell functions were cell autonomous, because dendritic cells from apoE(-/-) mice were able to activate B6 iNKT cells, but iNKT cells from apoE(-/-) mice were not able to respond to B6 dendritic cells.


CONCLUSIONS
These data suggest that chronic dyslipidemia induces an iNKT cell phenotype that is unresponsive to further simulation by exogenous glycolipid and that sustained unresponsiveness is iNKT cell intrinsic.
Braun
Nicole A
NA
Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Mendez-Fernandez
Yanice V
YV
Covarrubias
Roman
R
Porcelli
Steven A
SA
Savage
Paul B
PB
Yagita
Hideo
H
Van Kaer
Luc
L
Major
Amy S
AS
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000954:Antigens, Surface / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D002908:Chronic Disease; D017635:Clonal Anergy; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005699:Galactosylceramides / Q000008:administration & dosage; D006949:Hyperlipidemias / Q000235:genetics / Q000276:immunology*; D007274:Injections, Intraperitoneal; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000378:metabolism; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000276:immunology*; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013997:Time Factors
D000954:Antigens, Surface; D001057:Apolipoproteins E; D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D005699:Galactosylceramides; D007376:Interleukin-2; D055650:NK Cell Lectin-Like Receptor Subfamily A; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell; C493154:alpha-galactosylceramide