HIVEP3 inhibits fate decision of CD8+ invariant NKT cells after positive selection

Qielan Wu; Shiyu Bai; Miya Su; Yuwei Zhang; Xuran Chen; Ting Yue; Linfeng Xu; Lu Wang; Di Xie; Shuhang Li; Xiang Li; Sicheng Fu; Lili Wang; Chenxi Tian; Jun Pan; Yuanyuan Huang; Yuting Cai; Yu Wang; Fang Hu; Fengyin Li; Huimin Zhang; Li Bai

doi:10.1093/jleuko/qiad082

HIVEP3 inhibits fate decision of CD8+ invariant NKT cells after positive selection

J Leukoc Biol. 2023 Sep 27;114(4):335-346. doi: 10.1093/jleuko/qiad082.

Authors

Qielan Wu^{1

2}, Shiyu Bai^{1

2}, Miya Su^{1

2}, Yuwei Zhang^{1

2}, Xuran Chen^{1

2}, Ting Yue², Linfeng Xu², Lu Wang³, Di Xie^{1

2}, Shuhang Li^{1

2}, Xiang Li^{1

2}, Sicheng Fu^{1

2}, Lili Wang^{1

2}, Chenxi Tian^{1

2}, Jun Pan^{1

2}, Yuanyuan Huang^{1

2}, Yuting Cai^{1

2}, Yu Wang^{1

2}, Fang Hu^{1

2}, Fengyin Li^{1

2}, Huimin Zhang^{1

2}, Li Bai^{1

2

4

5}

Affiliations

¹ Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, No. 443 Huangshan Street, Shushan District, Hefei 230027, China.
² Biomedical Sciences and Health Laboratory of Anhui Province, Division of Life Sciences and Medicine, University of Science and Technology of China, No. 443 Huangshan Street, Shushan District, Hefei 230027, China.
³ Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Institute of Molecular Medicine, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160 Pujian Road, Pudong Disctrict, Shanghai 200127, China.
⁴ Institute of Health and Medicine, Hefei Comprehensive National Science Center, 4090 Susong Road, Shushan District, Hefei 230601, China.
⁵ National Synchrotron Radiation Laboratory, University of Science and Technology of China, No. 443 Huangshan Street, Shushan District, Hefei 230027, China.

PMID: 37479674
DOI: 10.1093/jleuko/qiad082

Abstract

CD8+ invariant natural killer T (iNKT) cells are functionally different from other iNKT cells and are enriched in human but not in mouse. To date, their developmental pathway and molecular basis for fate decision remain unclear. Here, we report enrichment of CD8+ iNKT cells in neonatal mice due to their more rapid maturation kinetics than CD8- iNKT cells. Along developmental trajectories, CD8+ and CD8- iNKT cells separate at stage 0, following stage 0 double-positive iNKT cells, and differ in HIVEP3 expression. HIVEP3 is lowly expressed in stage 0 CD8+ iNKT cells and negatively controls their development, whereas it is highly expressed in stage 0 CD8- iNKT cells and positively controls their development. Despite no effect on IFN-γ, HIVEP3 inhibits granzyme B but promotes interleukin-4 production in CD8+ iNKT cells. Together, we reveal that, as a negative regulator for CD8+ iNKT fate decision, low expression of HIVEP3 in stage 0 CD8+ iNKT cells favors their development and T helper 1-biased cytokine responses as well as high cytotoxicity.

Keywords: CD8+ iNKT; HIVEP3; IL-4; IL-7R; cell survival; fate decision; granzyme B; scRNA-seq.

Abstract

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