Genomic dissection of immunity in its tissue context

Cells of the immune system routinely respond to cues from their environment and feedback to their surrounding through means such as activation of signaling cascades and metabolic functions, migration, transient changes to cell state, longer-term fate decisions, and other forms of adaptation.  Over the years, our lab developed and applied computational tools that leverage techniques for high throughput molecular and cellular profiling (including single cell genomics)  in order to study how cells of the adaptive immune system respond to their environment. Our studies focused primarily on transcriptional control of T cell differentiation, heterogeneity and regulation of critical phenotypes of mature T cell populations, and the pertaining association with autoimmunity and aging. We were able to identify a number of mechanisms in these and other studies, through the activity of transcription factors, non-coding regions, signaling molecules, and metabolic enzymes.

While single cell genomics is routinely used to refine our understanding of the milieu of cell states in tissues, relating this information to the spatial context remains a major challenge. Our vision in this domain is to advance our understanding of immune function by leveraging nascent protocols for spatially resolved transcriptomics and by developing the accompanying computational tools. 

As part of this program, we apply experimental in situ technologies to study a number of outstanding questions in tumor biology, autoimmunity and lymphocyte development. By combining spatial transcriptomics with tools for deep generative modeling we seek to decipher how tumors achieve immune evasion by rendering tumor-infiltration leukocytes inactive, how immune-epithelial cross talk changes during gut inflammation, and how the developing T cell repertoire is shaped locally in the thymus.

Our work on computational tools, which draws on advances in generative modeling and computer vision, aims to provide effective ways for deriving insight from the data and for estimating the statistical credibility for those insights. To name a few of the major questions: (1) what is the structure of a tissue and what characterizes the cellular composition of each area? (2) which gene programs influence or are influenced by the immediate environment of cells of different types? (3) which inter-cellular cues (e.g. metabolic stresses) \ are associated with these programs? (4) which subsets of cells may be influencing each other (by physical contact or otherwise) and what are the consequences of these interactions? (5) how do these properties change between different conditions? And finally (6) how to study all that while accounting for the technical limitations of spatial transcriptomics, with hurdles such as batch effects, segmentation errors and measurement noise. 
 

 

 

 

 

Relevant publications

  • Multimodal profiling reveals tissue-directed signatures of human immune cells altered with age. SB. Wells*, DB. Rainbow*, M. Mark*, PA. Szabo*, C. Ergen*, A. Maceiras*, DP. Caron, E. Rahmani, E. Benuck, V. Pour Amiri, D. Chen, A. Wagner, SK. Howlett, LB. Jarvis, KL. Ellis, M. Kubota, R. Matsumoto, K. Mahbubani, K. Saeb-Parsy, C. Dominguez-Conde, L. Richardson, C. Xu, S. Li, L. Mamanova, L. Bolt, A. Wilk, SA. Teichmann†, DL. Farber†, PA. Sims†, JL. Jones†, N. Yosef† (bioRxiv)
     
  • NF-κB inhibitor alpha has a cross-variant role during SARS-CoV-2 infection in ACE2-overexpressing human airway organoids CR. Simoneau*, P. Chen*, GK. Xing*, MM. Khalid, NL. Meyers, JM. Hayashi, TY. Taha, KE. Leon, T. Ashuach, KA. Fontaine, L. Rodriguez, B. Joehnk, K. Walcott, S. Vasudevan, X. Fang, M. Maishan, S. Schultz, J. Roose, MA. Matthay, A. Sil, M. Arjomandi, N. Yosef†, M. Ott†. Scientific Reports, 2024. 10.1038/s41598-024-66003-2
     
  • Single-cell multi-omic analysis of thymocyte development reveals NFAT as a driver of CD4/CD8 lineage commitment Z. Steier, LL. McIntyre, LK. Lutes, T Huang, EA. Robey†, N. Yosef†, A. Streets† Nature Immunology, 2023
     
  • Hepatitis C virus infects and perturbs liver stem cells. NL. Meyers, T. Ashuach, DE. Lyons, MM. Khalid, CR. Simoneau, AL. Erickson, M. Bouhaddou, TT. Nguyen, GR. Kumar, TY. Taha, V. Natarajan, JL. Baron, N. Neff, F. Zanini, T. Mahmoudi, SR. Quake, NJ. Krogan, S. Cooper, TC. McDevitt, N. Yosef†, M. Ott†. mBio 2023
     
  • Induction of a colitogenic phenotype in Th1 cells depends on interleukin 23 receptor signaling. M. Pawlak*, D. DeTomaso*, GM. zu Horste, Y. Lee, J. Nyman, D. Dionne, C. Wang, A. Wallrapp, PR. Burkett, SJ. Riesenfeld, AC. Anderson, A. Regev, RJ. Xavier, N. Yosef†, VK. Kuchroo† Immunity, 2022

  • Batf-mediated Epigenetic Control of Effector CD8+ T Cell Differentiation.
    H.W. Tsao*, J. Kaminski*, M. Kurachi, R.A. Barnitz, M.A. DiIorio, M.W. LaFleur, W. Ise, T. Kurosaki, E.J. Wherry, W.N. Haining †, N. Yosef † Science Immunology, 2022

  • Multi-resolution deconvolution of spatial transcriptomics data reveals continuous patterns of inflammation. R. Lopez, B. Li, H. Keren-Shaul, P. Boyeau, M. Kedmi, D. Pilzer, A.Jelinski, E. David, A. Wagner, Y. Addadi, M.I. Jordan, I. Amit †, N. Yosef †. Nature Biotechnology, 2022

  • Massively parallel reporter perturbation assay uncovers temporal regulatory architecture during neural differentiation. A. Kreimer*, T. Ashuach*, F. Inoue*, A. Khodaverdian, N. Yosef †, N Ahituv †. Nature Communications, 2022

  • Metabolic modeling of single Th17 cells reveals regulators of autoimmunity. A. Wagner*, C. Wang*, D. DeTomaso, J. Avila-Pacheco, S. Zaghouani, J. Fessler, E. Akama-Garren, K. Pierce, N. Ron-Harel, V. Paraskevi Douglas, M. Haigis, R.A. Sobel, C. Clish, A. Regev, V.K. Kuchroo †, N. Yosef †. Cell 2021; S0092-8674(21)00700-5. doi: 10.1016/j.cell.2021.05.045

  • Oleic acid restores suppressive defects in tissue-resident FOXP3 Tregs from patients with multiple sclerosis. SL. Pompura*, A. Wagner*, A. Kitz, J. LaPerche, N. Yosef †, M. Dominguez-Villar †, DA, Hafler†. J Clin Invest. 2020. 131(2):e138519. doi: 10.1172/JCI138519.

  • Integrated single cell analysis of blood and cerebrospinal fluid leukocytes in multiple sclerosis. D. Schafflick* , C. Xu* , M. Hartlehnert* , M. Cole* , T. Lautwein, K. Buscher, J.Wolbert, SG. Meuth, T. Kuhlmann, C. Gross, H. Wiendl, N. Yosef † , G.M zu Horste † Nature Communications 2020. 14;11(1):247. doi: 10.1038/s41467-019-14118-w.

  • A Reproducibility-Based Computational Framework Identifies An Inducible Enhanced Antiviral Dendritic Cell State In HIV-1 Elite Controllers/ E.M. Gayo*, M.B. Cole*, K.E. Kolb*, Z. Ouyang, J. Cronin, S.W. Kazer, J. Ordovas-Montanes, M. Lichterfeld, B.D. Walker, N. Yosef†, A.K. Shalek†, and X.G. Yu†.  Genome Biology (2018) doi:10.1186/s13059-017-1385-x

  • Targeted reconstruction of T cell receptor sequence from single cell RNA-seq links CDR3 length to differentiation state/ S. Afik, K. Yates, K Bi, S. Darko, J. Godec, U. Gerdemann, L. Swadling, DC. Douek, P. Klenerman, EJ. Barnes, AH. Sharpe, N. Haining†, N. Yosef†.  Nucleic Acids Research 2017. doi.org/10.1093/nar/gkx615

  • The Epigenetic Landscape of T Cell Exhaustion/ D.R. Sen*, J. Kaminski*, R.A Barnitz, M. Kurachi, U. Gerdemann, K.B. Yates, H Tsao, J. Godec, M.W. LaFleur, F.D. Brown, P. Tonnerre, R.T. Chung, D.C. Tully, T.M. Allen, N. Frahm, G.M. Lauer, E. J. Wherry, N. Yosef†, W.N. Haining†.  Science 2016. DOI: 10.1126/science.aae0491

  • Writ large: Genomic Dissection of the Effect of Cellular Environment on Immune Response/N. Yosef†, A. Regev†. Science 2016.  354(6308): 64-68. DOI: 10.1126/science.aaf5453

  • Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity/ JT. Gaublomme*, N. Yosef*, Y. Lee, RS. Gertner, LV. Yang, PP. Pandolfi, T. Mak, R. Satija, AK. Shalek, VK. Kuchroo, A. Regev, H. Park. Cell. 2015; 163(6):1400-12
     
  • Small-Molecule RORγt Antagonists Inhibit T Helper 17 Cell Transcriptional Network by Divergent Mechanisms / S. Xiao*, N. Yosef*, J. Yang, Y. Wang, L. Zhou, C. Zhu, E Baloglu, D. Schmidt, R. Ramesh, M. Lobera, M.S. Sundrud, P. Tsai, Z. Xiang, J. Wang, Y. Xu, X. Lin, K. Kretschmer, P.B. Rahl, R.A. Young, Z. Zhong, D.A. Hafler, A. Regev, S. Ghosh, A. Marson, V.K. Kuchroo. Immunity 2014 Apr 17;40(4):477-89

  • Dynamic regulatory network controlling TH17 cell differentiation / N. Yosef*, A.K. Shalek*, J. Gaublomme*, Y. Lee, A. Awasthi, H. Jin, C. Wu, K. Karwacz, S. Xiao, M. Jorgolli, D. Gennert, R. Satija, A. Shakya, D.Y. Lu, J.J. Trombetta, M. Pillai, P.J. Ratcliffe, M.L. Coleman, M. Bix, D. Tantin, H. Park, V.K Kuchroo, A. Regev. Nature  2013 Apr 25;496(7446):461-8.

  • Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1/ C. Wu*, N. Yosef*, T. Thalhamer*, C. Zhu, S. Xiao, Y. Kishi, A. Regev, V.K. Kuchroo. Nature 2013 Apr 25;496(7446):513-7
     
  • A high throughput in vivo protein-DNA mapping approach reveals principles of dynamic gene regulation in mammals/ M. Garber*, N. Yosef*, A. Goren, R. Raychowdhury, A. Thielke, M. Guttman, J. Robinson, B. Minie, N. Chevrier, Z. Itzhaki, A. Weiner, D. Friedrich, J. Meldrim, O. Ram, C. Chang, A. Gnirke, S. Fisher, N. Friedman, B. Wong, B. Bernstein, C. Nusbaum, N. Hacohen, A. Regev, I. Amit. Molecular Cell. 47(5);810-22, 2012.