Human Immunology
(Single Cell Immunology)

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Recent advances in single cell technologies such as mass cytometry and single cell RNA-Seq have revealed high levels of heterogeneity among immune cells. Accordingly, Foxp3 expressing CD4+ regulatory T-cells (Tregs) need to adapt to diverse immunological environments Tregs themselves must show a diversity of functional states. Recent evidence demonstrates that Tregs partially mirror the phenotype of effector T-cell subset such as Th1, Th17 and Tfh cells.

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Figure 1. Treg diversity
From Wing et al. Front Imm 2012

In particular, T-follicular regulatory cells (Tfr) expressing the Tfh lineage defining transcription factor BCL6 are able to gain expression of the chemokine receptor CXCR5 and travel to the B-cell follicle where they act to suppress antibody production. Previously we have demonstrated that Tregs and Tfr control the formation of T-follicular helper cells and the resulting B-cell germinal center reaction via the co-inhibitory receptor CTLA-4 (Wing et al, Immunity 2014). Recently we found that there is a fundamental split in effector Treg subtypes with BCL6 expressing Tfr forming an IL-2 inhibited branch requiring them to downregulate the canonical Treg marker CD25 (IL2RA) in order to reach the germinal center (Wing et al, PNAS 2017). We have also found CXCR5 expressing Tfr like cells present in human blood.

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Figure 2: Main Treg subgroups present in human blood and tumors
From Wing et al. Immunity 2019

Given the complexity of the underlying biology a high dimensional approach, using mass cytometry (CyTOF), has many benefits for both the understanding of Treg heterogeneity and characterising the wide ranging effects of their impairment. Currently we are applying mass cytometry and other single cell techniques to a number of issues such as to explore the diversity of Tregs and consequences of Treg impairment in a variety of settings such as autoimmunity and cancer (Wing et al, Immunity 2019).

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Figure 3. Upper panel FlowSOM analysis of changes to CD4 T-cells post Treg depletion.
Lower panel, diversity of CD4+ Tumor infiltrating T-cells examined by Mass cytometry

Principal Investigator

James Badger Wing Associate Professor

Research field:Mass Cytometry, Immune regulation, T-cell-B-cell interactions.
+81-6-6879-4936
jbwingifrec.osaka-u.ac.jp
Education history
2003-2007 PhD University of Sheffield: Sheffield, UK
1999-2003 Degree in medical microbiology, University of Surrey, Guildford, UK
Research and career history
2019 - Associate Professor (Human Immunology) IFReC, Osaka University
2017 to 2019 Associate Professor (Experimental Immunology) IFReC, Osaka University
2012 to 2017 Assistant Professor (Experimental Immunology) IFReC, Osaka University
2010 to 2012 JSPS fellow (Experimental Immunology) IFReC, Osaka University
2008 to 2010 Post-doctoral research fellow. University of Sheffield: Sheffield, UK

Members

Janyerkye Tulyeu Researcher
janyerkyeifrec.osaka-u.ac.jp
Jonas N. Søndergaard Researcher
jonasifrec.osaka-u.ac.jp
Rika Ishii Laboratory Technician
rish226ifrec.osaka-u.ac.jp
 
 

Publications

Wing, JB., Tanaka, A., & Sakaguchi, S. Human FOXP3+ Regulatory T Cell Heterogeneity and Function in Autoimmunity and Cancer. Immunity, 2019, 50(2), 302–316. Review DOI/10.1016/J.IMMUNI.2019.01.020
Cossarizza A,…150 authors…,Wing, JB….16 authors… Zychlinsky A. Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition). Eur J Immunol. 2019 Oct;49(10):1457-1973. doi: 10.1002/eji.201970107.
Wing, JB., Tekgüç, M., & Sakaguchi, S. Control of Germinal Center Responses by T-Follicular Regulatory Cells. Frontiers in Immunology, 2018, 9, 1910. Review. DOI/10.3389/fimmu.2018.01910
Ha, D., Tanaka, A., Kibayashi, T., Tanemura, A., Sugiyama, D., Wing, JB., … 6 authors… Sakaguchi, S. (2019). Differential control of human Treg and effector T cells in tumor immunity by Fc-engineered anti-CTLA-4 antibody. Proc Natl Acad Sci U S A. 2019. 116(2), 609–618. DOI/10.1073/pnas.1812186116
Wing JB, Kitagawa Y, Locci M, Hume H, Tay C, Morita T, Kidani Y, Matsuda K, Inoue T, Kurosaki T, Crotty S, Coban C, Ohkura N, Sakaguchi S. A distinct subpopulation of CD25- T-follicular regulatory cells localizes in the germinal centers. Proc Natl Acad Sci U S A. 2017 Jul 11. pii: 201705551. DOI: 10.1073/pnas.1705551114.
Glatman Zaretsky, A., C. Konradt, F. Depis, Wing JB, R. Goenka, DG. Atria, JS. Silver, S. Cho, AI. Wolf, WJ. Quinn, JB. Engiles, DC. Brown, D. Beiting, J. Erikson, D. Allman, MP. Cancro, S. Sakaguchi, LF. Lu, CO. Benoist, and CA. Hunter. T Regulatory Cells Support Plasma Cell Populations in the Bone Marrow. Cell Rep, 2017. 18(8): p. 1906-1916. DOI: 10.1016/j.celrep.2017.01.067.
Morita, T., Y. Shima, Wing JB, S. Sakaguchi, A. Ogata, and A. Kumanogoh. The Proportion of Regulatory T Cells in Patients with Rheumatoid Arthritis: A Meta-Analysis. PloS one, 2016. 11(9). DOI: 10.1371/journal.pone.0162306.
Ohnmacht, C., J.H. Park, S. Cording, Wing JB, K. Atarashi, Y. Obata, V. Gaboriau-Routhiau, R. Marques, S. Dulauroy, M. Fedoseeva, M. Busslinger, N. Cerf-Bensussan, I.G. Boneca, D. Voehringer, K. Hase, K. Honda, S. Sakaguchi, and G. Eberl. MUCOSAL IMMUNOLOGY. The microbiota regulates type 2 immunity through RORgammat(+) T cells. Science, 2015. 349(6251): p. 989-93 DOI: 10.1126/science.aac4263.
Schubert, D., C. Bode, R. Kenefeck, T.Z. Hou, Wing JB, …34 authors…, B. Grimbacher. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nature medicine, 2014. 20(12): p. 1410-6. DOI: 10.1038/nm.3746.
Maeda, Y., H. Nishikawa, D. Sugiyama, D. Ha, M. Hamaguchi, T. Saito, M. Nishioka, Wing JB, D. Adeegbe, I. Katayama, and S. Sakaguchi. Detection of self-reactive CD8(+) T cells with an anergic phenotype in healthy individuals. Science, 2014. 346(6216): p. 1536-40. DOI: 10.1126/science.aaa1292.
Wing JB, W. Ise, T. Kurosaki, and S. Sakaguchi. Regulatory T cells control antigen-specific expansion of Tfh cell number and humoral immune responses via the coreceptor CTLA-4. Immunity, 2014. 41(6): p. 1013-25. DOI: 10.1016/j.immuni.2014.12.006.
Wing JB, Smart L, Borrow R, Findlow J, Findlow H, Heath AW, Read RC. Kinetics of immune responses to nasal challenge with meningococcal polysaccharide one year after serogroup-C glycoconjugate vaccination. Clin Infect Dis. 2011 Jun;52(11): p. 1317-23. DOI: 10.1093/cid/cir198
Wing JB*, Darton TC*, Lees A, Heath AW, Read RC. Adult survivors of invasive pneumococcal disease exhibit defective B cell function. Clin Infect Dis. 2011 May;52(9): p. 1133-6. DOI: 10.1093/cid/cir126. *Joint first authors.