TY - JOUR
T1 - Mechanisms for glycolipid antigen-driven cytokine polarization by Vα14i NKT cells
AU - Sullivan, Barbara A.
AU - Nagarajan, Niranjana A.
AU - Wingender, Gerhard
AU - Wang, Jing
AU - Scott, Iain
AU - Tsuji, Moriya
AU - Franck, Richard W.
AU - Porcelli, Steven A.
AU - Zajonc, Dirk M.
AU - Kronenberg, Mitchell
PY - 2010/1/1
Y1 - 2010/1/1
N2 - Certain glycolipid Ags for Vα14i NKT cells can direct the overall cytokine balance of the immune response. Th2-biasing OCH has a lower TCR avidity than the most potent agonist known, α-galactosylceramide. Although the CD1d-exposed portions of OCH and α-galactosylceramide are identical, structural analysis indicates that there are subtle CD1d conformational differences due to differences in the buried lipid portion of these two Ags, likely accounting for the difference in antigenic potency. Th1-biasing C-glycoside/ CD1d has even weaker TCR interactions than OCH/CD1d. Despite this, C-glycoside caused a greater downstream activation of NK cells to produce IFN-γ, accounting for its promotion of Th1 responses. We found that this difference correlated with the finding that C-glycoside/CD1d complexes survive much longer in vivo. Therefore, we suggest that the pharmacokinetic properties of glycolipids are a major determinant of cytokine skewing, suggesting a pathway for designing therapeutic glycolipids for modulating invariant NKT cell responses.
AB - Certain glycolipid Ags for Vα14i NKT cells can direct the overall cytokine balance of the immune response. Th2-biasing OCH has a lower TCR avidity than the most potent agonist known, α-galactosylceramide. Although the CD1d-exposed portions of OCH and α-galactosylceramide are identical, structural analysis indicates that there are subtle CD1d conformational differences due to differences in the buried lipid portion of these two Ags, likely accounting for the difference in antigenic potency. Th1-biasing C-glycoside/ CD1d has even weaker TCR interactions than OCH/CD1d. Despite this, C-glycoside caused a greater downstream activation of NK cells to produce IFN-γ, accounting for its promotion of Th1 responses. We found that this difference correlated with the finding that C-glycoside/CD1d complexes survive much longer in vivo. Therefore, we suggest that the pharmacokinetic properties of glycolipids are a major determinant of cytokine skewing, suggesting a pathway for designing therapeutic glycolipids for modulating invariant NKT cell responses.
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U2 - 10.4049/jimmunol.0902880
DO - 10.4049/jimmunol.0902880
M3 - Article
C2 - 19949076
AN - SCOPUS:73949148254
SN - 0022-1767
VL - 184
SP - 141
EP - 153
JO - Journal of Immunology
JF - Journal of Immunology
IS - 1
ER -