Single-cell transcriptomic profiling reveals a pathogenic role of cytotoxic CD4+ T cells in giant cell arteritis
Carmona, Elio G. (Hospital Universitario San Cecilio (Granada))
Callejas Rubio, Jose Luis (Hospital Universitario San Cecilio (Granada))
Raya, Enrique (Hospital Universitario San Cecilio (Granada))
Ríos-Fernández, Raquel (Hospital Universitario San Cecilio (Granada))
Villanueva-Martín, Gonzalo (Institute of Parasitology and Biomedicine López-Neyra)
Cid, María (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Hernández-Rodríguez, José (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Ballestar, Esteban (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Timmermann, Bernd (Max Planck Institute for Molecular Genetics)
Ortego-Centeno, Norberto (Universidad de Granada. Departamento de Medicina)
Martín, Javier (Spanish National Research Council)
Márquez, Ana (Instituto de Parasitología y Biomedicina "López-Neyra")

Data:	2024
Resum:	Giant cell arteritis (GCA) is a systemic vasculitis mediated by an aberrant immunological response against the blood vessel wall. Although the pathogenic mechanisms that drive GCA have not yet been elucidated, there is strong evidence that CD4 T cells are key drivers of the inflammatory process occurring in this vasculitis. The aim of this study was to further delineate the role of CD4 T cells in GCA by applying single-cell RNA sequencing and T cell receptor (TCR) repertoire profiling to 114. 799 circulating CD4 T cells from eight GCA patients in two different clinical states, active and in remission, and eight healthy controls. Our results revealed an expansion of cytotoxic CD4 T lymphocytes (CTLs) in active GCA patients, which expressed higher levels of cytotoxic and chemotactic genes when compared to patients in remission and controls. Accordingly, differentially expressed genes in CTLs of active patients were enriched in pathways related to granzyme-mediated apoptosis, inflammation, and the recruitment of different immune cells, suggesting a role of this cell type in the inflammatory and vascular remodelling processes occurring in GCA. CTLs also exhibited a higher clonal expansion in active patients with respect to those in remission. Drug repurposing analysis prioritized maraviroc, which targeted CTLs, as potentially repositionable for this vasculitis. In addition, effector regulatory T cells (Tregs) were decreased in GCA and showed lower expression of genes involved in their suppressive activity. These findings provide further insights into the pathogenic role of CD4 T cells in GCA and suggest targeting CTLs as a potential therapeutic option.
Ajuts:	Instituto de Salud Carlos III RD21/0002/0039 Instituto de Salud Carlos III PI18/00040
Nota:	This work was supported by the Instituto de Salud Carlos III (PI18/00040 and Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) (RD21/0002/0039)).
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Journal of autoimmunity, Vol. 142 (january 2024) , p. 103124, ISSN 1095-9157

DOI: 10.1016/j.jaut.2023.103124

12 p, 9.5 MB

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Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Institut de Recerca contra la Leucèmia Josep Carreras
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