Open AccessA Designed α ‐GalCer Analog Promotes Considerable Th1 Cytokine Response by Activating the CD1d‐iNKT Axis and CD11b‐Positive Monocytes/Macrophages
Author(s) -
Ma Juan,
He Peng,
Zhao Chuanfang,
Ren Quanzhong,
Dong Zheng,
Qiu Jiahuang,
Jing Yang,
Liu Sijin,
Du Yuguo
Publication year - 2020
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202000609
Subject(s) - cd1d , priming (agriculture) , dendritic cell , t cell , t cell receptor , microbiology and biotechnology , cytokine , immunology , chemistry , biology , immune system , botany , germination
Selective helper T cell 1 (Th1) priming agonists are a promising area of investigation for immunotherapeutic treatment of various diseases. α ‐galactosylceramide ( α ‐GalCer, KRN7000), a well‐studied Th1‐polarizer, simultaneously induces helper T cell 2 (Th2)‐type responses, which is a major drawback for its clinical applications. Based on surflex‐docking computation, α ‐GalCer‐diol, with added hydroxyl groups in the acyl chain, is designed and synthesized. Structural analyses reveal stronger affinity between α ‐GalCer‐diol and cluster of differentiation 1d (CD1d), leading to enhanced antigen presentation by dendritic cells (DCs) and self‐activation, as reflected by tight binding of the T‐cell receptor (TCR)/KRN7000/CD1d ternary complex and elevated production of interleukin 12 (IL‐12) and interferon‐ γ (IFN‐ γ ). Consequently, invariant natural killer T cells (iNKTs) are activated and exhibit an improved Th1‐type cytokine profile ex vivo and in vivo. Different from KRN7000, α ‐GalCer‐diol markedly boosts the expansion of the CD11b + subpopulation and enhances IFN‐ γ content in CD11b + cells. These reinforced Th1‐type responses collectively endow α ‐GalCer‐diol more robust antitumor activity in a xenograft animal model using B16‐F10 melanoma cells. Together, the data demonstrate a new mechanism through which α ‐GalCer‐diol induces stronger Th1‐type responses by stimulating CD11b + leukocyte expansion and DC‐conducted CD1d‐restricted and TCR‐mediated iNKT activation. Hence, this study may facilitate the development of novel Th1 priming agonists.