GM-CSF and CXCR4 define a T helper cell signature in multiple sclerosis

• Published in: Nature medicine Vol. 25; no. 8; pp. 1290 - 1300
• Main Authors: Galli, Edoardo, Hartmann, Felix J., Schreiner, Bettina, Ingelfinger, Florian, Arvaniti, Eirini, Diebold, Martin, Mrdjen, Dunja, van der Meer, Franziska, Krieg, Carsten, Nimer, Faiez Al, Sanderson, Nicholas, Stadelmann, Christine, Khademi, Mohsen, Piehl, Fredrik, Claassen, Manfred, Derfuss, Tobias, Olsson, Tomas, Becher, Burkhard
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2019; Nature Publishing Group
• Subjects: 631/114; 631/250/127; 631/250/1619/554/1898; 692/53; 692/699/375/1666; Algorithms; Antigens; Autoimmune diseases; Biomedical and Life Sciences; Biomedicine; Cancer Research; Central nervous system; Cerebrospinal fluid; Chemokines; Colony-stimulating factor; CXCR4 protein; Cytokines; Cytokines - biosynthesis; Cytometry; Genetic aspects; Granulocyte-macrophage colony-stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor - biosynthesis; Helper cells; Humans; Immunologic Memory; Infectious Diseases; Inflammatory diseases; Interferon; Learning algorithms; Lymphocytes; Lymphocytes T; Machine learning; Medicin och hälsovetenskap; Metabolic Diseases; Molecular Medicine; Multiple sclerosis; Multiple Sclerosis - cerebrospinal fluid; Multiple Sclerosis - immunology; Neural networks; Neurosciences; Peripheral blood; Receptors, CXCR4 - biosynthesis; Risk factors; T-Lymphocytes, Helper-Inducer - immunology; Therapeutic applications
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-019-0521-4

Cytokine dysregulation is a central driver of chronic inflammatory diseases such as multiple sclerosis (MS). Here, we sought to determine the characteristic cellular and cytokine polarization profile in patients with relapsing–remitting multiple sclerosis (RRMS) by high-dimensional single-cell mass cytometry (CyTOF). Using a combination of neural network-based representation learning algorithms, we identified an expanded T helper cell subset in patients with MS, characterized by the expression of granulocyte–macrophage colony-stimulating factor and the C-X-C chemokine receptor type 4. This cellular signature, which includes expression of very late antigen 4 in peripheral blood, was also enriched in the central nervous system of patients with relapsing–remitting multiple sclerosis. In independent validation cohorts, we confirmed that this cell population is increased in patients with MS compared with other inflammatory and non-inflammatory conditions. Lastly, we also found the population to be reduced under effective disease-modifying therapy, suggesting that the identified T cell profile represents a specific therapeutic target in MS. A machine learning approach using high-dimensional phenotypic and functional profiling data identifies a multiple sclerosis-specific T cell population that is reduced following treatment.