GBD 2016 Traumatic Brain Injury and Spinal Cord Injury Collaborators.Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990â2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 18, 56â87 (2019).
Daglas, M. et al. Activated CD8+ T cells cause long-term neurological impairment after traumatic brain injury in mice. Cell Rep. 29, 1178â1191.e6 (2019).
Moalem, G. et al. Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nat. Med. 5, 49â55 (1999).
Kipnis, J., Mizrahi, T., Yoles, E., Ben-Nun, A. & Schwartz, M. Myelin specific Th1 cells are necessary for post-traumatic protective autoimmunity. J. Neuroimmunol. 130, 78â85 (2002).
Miller, S. D., Karpus, W. J. & Davidson, T. S. Experimental autoimmune encephalomyelitis in the mouse. Curr. Protoc. Immunol. 88, 15.1.1â15.1.20 (2010).
Jager, A., Dardalhon, V., Sobel, R. A., Bettelli, E. & Kuchroo, V. K. Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J. Immunol. 183, 7169â7177 (2009).
Wei, S. C., Duffy, C. R. & Allison, J. P. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 8, 1069â1086 (2018).
June, C. H., OâConnor, R. S., Kawalekar, O. U., Ghassemi, S. & Milone, M. C. CAR T cell immunotherapy for human cancer. Science 359, 1361â1365 (2018).
Goverman, J. Autoimmune T cell responses in the central nervous system. Nat. Rev. Immunol. 9, 393â407 (2009).
Bradbury, E. J. & Burnside, E. R. Moving beyond the glial scar for spinal cord repair. Nat. Commun. 10, 3879 (2019).
Cohen, M. et al. Meningeal lymphoid structures are activated under acute and chronic spinal cord pathologies. Life Sci. Alliance 4, e202000907 (2021).
Crosby, C. M. & Kronenberg, M. Tissue-specific functions of invariant natural killer T cells. Nat. Rev. Immunol. 18, 559â574 (2018).
Klein, L., Klugmann, M., Nave, K. A., Tuohy, V. K. & Kyewski, B. Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells. Nat. Med. 6, 56â61 (2000).
Harrington, C. J. et al. Differential tolerance is induced in T cells recognizing distinct epitopes of myelin basic protein. Immunity 8, 571â580 (1998).
Miyauchi, E. et al. Gut microorganisms act together to exacerbate inflammation in spinal cords. Nature 585, 102â106 (2020).
ElTanbouly, M. A. & Noelle, R. J. Rethinking peripheral T cell tolerance: checkpoints across a T cellâs journey. Nat. Rev. Immunol. 21, 257â267 (2021).
Holst, J. et al. Generation of T-cell receptor retrogenic mice. Nat. Protoc. 1, 406â417 (2006).
Basso, D. M. et al. Basso Mouse Scale for locomotion detects differences in recovery after spinal cord injury in five common mouse strains. J. Neurotrauma 23, 635â659 (2006).
Andreatta, M. et al. A CD4+ T cell reference map delineates subtype-specific adaptation during acute and chronic viral infections. eLife 11, e76339 (2022).
Andreatta, M. et al. Interpretation of T cell states from single-cell transcriptomics data using reference atlases. Nat. Commun. 12, 2965 (2021).
Shechter, R. et al. Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med. 6, e1000113 (2009).
Muhl, H. & Pfeilschifter, J. Anti-inflammatory properties of pro-inflammatory interferon-γ. Int. Immunopharmacol. 3, 1247â1255 (2003).
Sosa, R. A., Murphey, C., Robinson, R. R. & Forsthuber, T. G. IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation. Proc. Natl Acad. Sci. USA 112, E5038âE5047 (2015).
Miller, N. M., Wang, J., Tan, Y. & Dittel, B. N. Anti-inflammatory mechanisms of IFN-γ studied in experimental autoimmune encephalomyelitis reveal neutrophils as a potential target in multiple sclerosis. Front. Neurosci. 9, 287 (2015).
Butovsky, O. et al. Microglia activated by IL-4 or IFN-γ differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol. Cell. Neurosci. 31, 149â160 (2006).
Butovsky, O. et al. Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis. J. Clin. Invest. 116, 905â915 (2006).
Shaked, I. et al. Protective autoimmunity: interferon-γ enables microglia to remove glutamate without evoking inflammatory mediators. J. Neurochem. 92, 997â1009 (2005).
Mojic, M., Takeda, K. & Hayakawa, Y. The dark side of IFN-γ: its role in promoting cancer immunoevasion. Int. J. Mol. Sci. 19, 89 (2017).
Zhao, H. et al. Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduct. Target. Ther. 6, 263 (2021).
Jing, Z. L. et al. Interferon-γ in the tumor microenvironment promotes the expression of B7H4 in colorectal cancer cells, thereby inhibiting cytotoxic T cells. Sci. Rep. 14, 6053 (2024).
Dorrier, C. E. et al. CNS fibroblasts form a fibrotic scar in response to immune cell infiltration. Nat. Neurosci. 24, 234â244 (2021).
Ise, W. et al. CTLA-4 suppresses the pathogenicity of self antigen-specific T cells by cell-intrinsic and cell-extrinsic mechanisms. Nat. Immunol. 11, 129â135 (2010).
Xu, M. et al. c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont. Nature 554, 373â377 (2018).
Petersen, T. R. et al. Characterization of MHC- and TCR-binding residues of the myelin oligodendrocyte glycoprotein 38â51 peptide. Eur. J. Immunol. 34, 165â173 (2004).
Wan, X. et al. Pancreatic islets communicate with lymphoid tissues via exocytosis of insulin peptides. Nature 560, 107â111 (2018).
Kacen, A. et al. Post-translational modifications reshape the antigenic landscape of the MHC I immunopeptidome in tumors. Nat. Biotechnol. 41, 239â251 (2023).
Pulous, F. E. et al. Cerebrospinal fluid can exit into the skull bone marrow and instruct cranial hematopoiesis in mice with bacterial meningitis. Nat. Neurosci. 25, 567â576 (2022).
Rustenhoven, J. et al. Functional characterization of the dural sinuses as a neuroimmune interface. Cell 184, 1000â1016.e27 (2021).
Glanville, J. et al. Identifying specificity groups in the T cell receptor repertoire. Nature 547, 94â98 (2017).
Kunis, G. et al. IFN-γ-dependent activation of the brainâs choroid plexus for CNS immune surveillance and repair. Brain 136, 3427â3440 (2013).
Gadani, S. P., Walsh, J. T., Smirnov, I., Zheng, J. & Kipnis, J. The glia-derived alarmin IL-33 orchestrates the immune response and promotes recovery following CNS injury. Neuron 85, 703â709 (2015).
Lima, R. et al. Systemic interleukin-4 administration after spinal cord injury modulates inflammation and promotes neuroprotection. Pharmaceuticals 10, 83 (2017).
McCarthy, D. J., Campbell, K. R., Lun, A. T. & Wills, Q. F. Scater: pre-processing, quality control, normalization and visualization of single-cell RNA-seq data in R. Bioinformatics 33, 1179â1186 (2017).
Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411â420 (2018).
Lun, A. T., McCarthy, D. J. & Marioni, J. C. A step-by-step workflow for low-level analysis of single-cell RNA-seq data with Bioconductor. F1000Res. 5, 2122 (2016).
Epskamp, S., Cramer, A. O. J., Waldorp, L. J., Schmittmann, V. D. & Borsboom, D. qgraph: Network visualizations of relationships in psychometric data. J. Stat. Softw. https://doi.org/10.18637/jss.v048.i04 (2012).
Bais, A. S. & Kostka, D. scds: Computational annotation of doublets in single-cell RNA sequencing data. Bioinformatics 36, 1150â1158 (2020).
Huang, H., Wang, C., Rubelt, F., Scriba, T. J. & Davis, M. M. Analyzing the Mycobacterium tuberculosis immune response by T-cell receptor clustering with GLIPH2 and genome-wide antigen screening. Nat. Biotechnol. 38, 1194â1202 (2020).
Van den Berge, K. et al. Observation weights unlock bulk RNA-seq tools for zero inflation and single-cell applications. Genome Biol. 19, 24 (2018).
Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139â140 (2010).
Hong, G., Zhang, W., Li, H., Shen, X. & Guo, Z. Separate enrichment analysis of pathways for up- and downregulated genes. J. R. Soc. Interface 11, 20130950 (2014).
Yu, G., Wang, L. G., Han, Y. & He, Q. Y.clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16, 284â287 (2012).
Baccin, C. et al. Combined single-cell and spatial transcriptomics reveal the molecular, cellular and spatial bone marrow niche organization. Nat. Cell Biol. 22, 38â48 (2020).
Korotkevich, G. et al. Fast gene set enrichment analysis. Preprint at bioRxiv https://doi.org/10.1101/060012 (2021).
