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CD7 activation regulates cytotoxicity-driven pathology in systemic sclerosis, yielding a target for selective cell depletion.
Papadimitriou, Theodoros Ioannis; Singh, Prashant; van Caam, Arjan; Walgreen, Birgitte; Gorris, Mark A J; Vitters, Elly L; van Ingen, Iris L; Koenders, Marije I; Smeets, Ruben L; Vonk, Madelon; de Vries, Jolanda M; van der Kraan, Peter M; van Oosterhout, Ypke; Huynen, Martijn A; Koenen, Hans J P M; Thurlings, Rogier M.
Afiliación
  • Papadimitriou TI; Department of Rheumatology, Radboudumc, Nijmegen, The Netherlands.
  • Singh P; Department of Laboratory Medicine - Medical Immunology, Radboudumc, Nijmegen, The Netherlands.
  • van Caam A; Department of Medical Biosciences, Radboudumc, Nijmegen, The Netherlands.
  • Walgreen B; Department of Rheumatology, Radboudumc, Nijmegen, The Netherlands.
  • Gorris MAJ; Department of Rheumatology, Radboudumc, Nijmegen, The Netherlands.
  • Vitters EL; Department of Medical Biosciences, Radboudumc, Nijmegen, The Netherlands.
  • van Ingen IL; Department of Medical BioSciences, Division of Immunotherapy, Oncode Institute, Radboudumc, Nijmegen, The Netherlands.
  • Koenders MI; Department of Rheumatology, Radboudumc, Nijmegen, The Netherlands.
  • Smeets RL; Department of Rheumatology, Radboudumc, Nijmegen, The Netherlands.
  • Vonk M; Department of Rheumatology, Radboudumc, Nijmegen, The Netherlands.
  • de Vries JM; Department of Laboratory Medicine - Medical Immunology, Radboudumc, Nijmegen, The Netherlands.
  • van der Kraan PM; Department of Laboratory Medicine - Radboudumc Laboratory for Diagnostics, Radboud University, Nijmegen, The Netherlands.
  • van Oosterhout Y; Department of Rheumatology, Radboudumc, Nijmegen, The Netherlands.
  • Huynen MA; Department of Medical Biosciences, Radboudumc, Nijmegen, The Netherlands.
  • Koenen HJPM; Department of Rheumatology, Radboudumc, Nijmegen, The Netherlands.
  • Thurlings RM; Philikos BV, Nijmegen, The Netherlands.
Ann Rheum Dis ; 83(4): 488-498, 2024 Mar 12.
Article en En | MEDLINE | ID: mdl-38123919
ABSTRACT

OBJECTIVES:

Cytotoxic T cells and natural killer (NK) cells are central effector cells in cancer and infections. Their effector response is regulated by activating and inhibitory receptors. The regulation of these cells in systemic autoimmune diseases such as systemic sclerosis (SSc) is less defined.

METHODS:

We conducted ex vivo analysis of affected skin and blood samples from 4 SSc patient cohorts (a total of 165 SSc vs 80 healthy individuals) using single-cell transcriptomics, flow cytometry and multiplex immunofluorescence staining. We further analysed the effects of costimulatory modulation in functional assays, and in a severely affected SSc patient who was treated on compassionate use with a novel anti-CD3/CD7 immunotoxin treatment.

RESULTS:

Here, we show that SSc-affected skin contains elevated numbers of proliferating T cells, cytotoxic T cells and NK cells. These cells selectively express the costimulatory molecule CD7 in association with cytotoxic, proinflammatory and profibrotic genes, especially in recent-onset and severe disease. We demonstrate that CD7 regulates the cytolytic activity of T cells and NK cells and that selective depletion of CD7+ cells prevents cytotoxic cell-induced fibroblast contraction and inhibits their profibrotic phenotype. Finally, anti-CD3/CD7 directed depletive treatment eliminated CD7+ skin cells and stabilised disease manifestations in a severely affected SSc patient.

CONCLUSION:

Together, the findings imply costimulatory molecules as key regulators of cytotoxicity-driven pathology in systemic autoimmune disease, yielding CD7 as a novel target for selective depletion of pathogenic cells.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Esclerodermia Sistémica / Linfocitos T Límite: Humans Idioma: En Revista: Ann Rheum Dis Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Esclerodermia Sistémica / Linfocitos T Límite: Humans Idioma: En Revista: Ann Rheum Dis Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Reino Unido