CD8(+)NKT-like cells regulate the immune response by killing antigen-bearing DCs.

Minghui Zhang,Qian Wang,Yewei Ji,Zhongli Zhu,Yunfeng Jiang,Zhenglong Yuan,Yijie Chai,Zhijie Chang,Xi Liu,Chao Wang,Ying Wan,Zhengyuan Li

doi:10.1038/srep14124

Minghui Zhang, Qian Wang + Show 10 more

Open Access

https://doi.org/10.1038/srep14124

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Abstract

CD1d-dependent NKT cells have been extensively studied; however, the function of CD8+NKT-like cells, which are CD1d-independent T cells with NK markers, remains unknown. Here, we report that CD1d-independent CD8+NKT-like cells, which express both T cell markers (TCRβ and CD3) and NK cell receptors (NK1.1, CD49b and NKG2D), are activated and significantly expanded in mice immunized with GFP-expressing dendritic cells. Distinct from CD1d-dependent NKT cells, CD8+NKT-like cells possess a diverse repertoire of TCRs and secrete high levels of IFN-gamma but not IL-4. CD8+NKT-like cell development is normal in CD1d−/− mice, which suggests that CD8+NKT-like cells undergo a unique development pathway that differs from iNKT cells. Further functional analyses show that CD8+NKT-like cells suppress T-cell responses through elimination of dendritic cells in an antigen-specific manner. Adoptive transfer of antigen-specific CD8+NKT-like cells into RIP-OVA mice prevented subsequent development of diabetes in the animals induced by activated OT-I CD8 T cells. Our study suggests that CD8+NKT-like cells can function as antigen-specific suppressive cells to regulate the immune response through killing antigen-bearing DCs. Antigen-specific down regulation may provide an active and precise method for constraining an excessive immune response and avoiding bypass suppression of necessary immune responses to other antigens.

Highlights

Immune regulation plays an important role in maintaining immune homeostasis and provides necessary protection from tissue damage caused by excessive immune responses
We focused on the CD1d-independent CD8+NKT-like cell subset and found that the cell number increased after vaccination with LPS-pulsed, GFP-expressing dendritic cells (GFP-DCs, wherein GFP can be presented as endogenous antigen)
Considering the close relationship between CD8-expressing lymphocytes and DCs loaded with an endogenous antigen, we speculated that CD8+NKT-like cells are activated and the cell number is increased by GFP-DCs

Summary

Introduction

Immune regulation plays an important role in maintaining immune homeostasis and provides necessary protection from tissue damage caused by excessive immune responses. Studies suggest that iNKT cells are involved in multiple aspects of the immune response, including inflammation, tumor immunology and immune regulation. An examination of NKT cell subsets in CD1d−/− mice revealed the CD1d-independent NKT cell subset; approximately 50% of the cells therein express CD816. Previous studies on the CD8+NKT-like cell subset have mainly focused on antitumor effects and demonstrate that these cells from both MHC-I-competent[18,20] and -deficient mice[19] produce high levels of IFN-γ and exhibit an effective tumoricidal capacity against tumor cells. We focused on the CD1d-independent CD8+NKT-like cell subset and found that the cell number increased after vaccination with LPS-pulsed, GFP-expressing dendritic cells (GFP-DCs, wherein GFP can be presented as endogenous antigen). Combined with evidence of their phenotypic, developmental and functional features, we conclude that CD8+NKT-like cells are distinct from previously identified iNKT and classical CD8 T cells; the cells suppress the immune response in an antigen-specific manner by effectively killing antigen-bearing DCs

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