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Variants of innate CD8+ T cells are associated with Grip2 and Klf15 genes

Cellular & Molecular Immunology volume 17, pages 1007–1009 (2020)Cite this article

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Lineage commitment of thymocytes can be distinguished and modulated by key factors of transcriptional networks, such as the antagonistic expression and function of Th-POK and Runx3 in the CD4 and CD8 lineages1 and Foxp32 and PLZF3 in CD4+ regulatory T (Treg) cells and natural killer T (NKT) cells, respectively. Little is known, however, about the transcriptional regulation of the innate T cell lineage, especially innate CD8+ T cells (i8Ts), which were initially defined in genetically manipulated mice4 and later in BALB/c mice5 and humans.6 i8Ts are nonconventional αβT cells that exhibit features of memory phenotype and are dependent on IL-4 produced by NKT cells.4 Although i8Ts are distinct from conventional memory CD8+ T cells, they do share markers of T cells undergoing homeostatic proliferation and activated CD8+ T cells.4,7 Thus, the identification of key determinants in i8T development is important to understand the molecular mechanisms underlying their development and responses. In this study, we investigated the genetics of i8T development by determining the frequency of i8Ts and NKT cells among Collaborative Cross (CC) strains. Using CC, a powerful genetic resource designed to facilitate rapid mapping of genes mediating complex traits,8,9 we identified key genes, Klf15 and Grip2, that are important in the development of i8Ts.

Next, the frequency of i8Ts was compared with the genotypes of each CC and founder strain. Mapping was performed using a logistic regression model (LRM) fit over the reconstructed haplotype matrix.8 The resulting genome-wide distribution of –log(P) values (ANOVA chi-squared) is shown in Fig. S2a, together with the FDR thresholds. The genome-wide scan for genetic loci associated with changes in i8Ts revealed a major peak on chromosome 6, centered at 93.7 Mb (Fig. S2b). Within the LOD-2 region (89.4–95.6 Mb), Klf15 was the only gene that had a nonsynonymous SNP in only the WSB and CAST strains, which had the highest i8T levels. The founder strain associated with the lowest levels of i8Ts, PWK, had 20 unique SNPs in the following genes within the peak region: Uroc1, Grip2, 4930590J08Rik, Fgd5, Adamts9, and Magi1 (Fig. S2c).

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Fig. 1: The identification of Grip2 and Klf15 associated with i8Ts in CC strains.

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Acknowledgements

We thank Drs. J.H. Park and Y.J. Lee for the critical review of this paper and members of the mouse core facility at PNU School of Medicine for taking care of our mice. This work was supported by the Medical Research Center (MRC) Program through the National Research Foundation of Korea (NRF) (grant number NRF-2015R1A5A2009656). We also thank Ben Ezzy, Kylee Parentich, Andrew Wallace, and Glynn Manship for providing animal care services. G.M. and L.B. are supported by grants from the Diabetes Research Foundation of Western Australia (Perth, WA, Australia).

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  1. These authors contributed equally: Yuna Jo, Lois Balmer

Authors and Affiliations

  1. Department of Anatomy, Pusan National University School of Medicine, Yangsan, 50612, South Korea

    Yuna Jo, Byunghyuk Lee, Ju A Shim, Laraib Amir Ali & Changwan Hong

  2. Centre for Diabetes Research, Harry Perkins Institute of Medical Research, Australia Centre of Medical Research, University of Western Australia, Nedlands, WA, 6009, Australia

    Lois Balmer & Grant Morahan

  3. School of Medical and Health Sciences, Edith Cowen University, Joondalup, WA, 6027, Australia

    Lois Balmer

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Contributions

Y.J. and C.H. designed the research, analyzed the data, and wrote the paper. Y.J., L.B., J.A.S., L.A.A. and B.L. performed the experiments and analyzed the data. G.M. designed the research and interpreted the data, and L.B. and G.M. reviewed the paper. All authors have read and approved the final paper.

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Correspondence to Grant Morahan or Changwan Hong.

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Jo, Y., Balmer, L., Lee, B. et al. Variants of innate CD8+ T cells are associated with Grip2 and Klf15 genes. Cell Mol Immunol 17, 1007–1009 (2020). https://doi.org/10.1038/s41423-019-0357-3

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