Memory CD4+ T cells lacking expression of CCR7 promote pro-inflammatory cytokine production in patients with diffuse cutaneous systemic sclerosis.

Abstract

Systemic sclerosis (SSc) is a predominantly T-cell-mediated autoimmune disorder with a characteristic sequence of Th1 and Th2 inflammation resulting in fibrosis. The contribution of differentiated memory T-cell subpopulations and methylation of CpG regions of Th1- or Th2-specific transcription factor genes on the inflammatory cytokine signature in SSc is not well understood. The study aimed to investigate phenotypic differentiation, the cytokine signature, sensitivity of memory T cells to in vitro suppression by autologous regulatory T cells (Tregs), and methylation of Th1- and Th2-specific transcription factor genes in patients with limited (lcSSc) and diffuse cutaneous SSc (dcSSc) compared to healthy donors (HD). Phenotype/intracellular cytokine production and methylation of Th1- and Th2-specific transcription factor genes were determined by flow cytometry and epigenetic analysis, respectively, and compared between patients with lcSSc, dcSSc and HD. Discrimination of CD4+ T cells that lack CCR7 expression revealed that CCR7- CD4+ memory T cells and effectors are producers of intracellular TNFα, IL-13 and IL-4, particularly in dcSSc. A proportional increase in CCR7- memory T cells was demonstrated by SSc-derived CD4+ T-cells after insufficient suppression by Tregs. A higher level of methylation of GATA3 or STAT4 (Th2- and Th1-specific transcription factor genes, respectively) was observed in dcSSc. An abundance of specific CD4+ memory T-cell subpopulations strongly contributes to the production of pro-inflammatory cytokines in dcSSc. Our results suggest that therapeutic concepts should focus more intensively on the memory phenotype to control T cell-mediated inflammation in SSc patients.

• Authors: Giovanni Almanzar, Marc Schmalzing, Matthias Klein, Deborah Hilligardt, Patrick Morris, Kerstin Höfner, Nady El Hajj, Hermann Kneitz, Vanessa Wild, Andreas Rosenwald, Sandrine Benoit, Henning Hamm, Hans-Peter Tony, Thomas Haaf, Matthias Goebeler, Martina Prelog
• Journal: European journal of dermatology : EJD (Eur J Dermatol) Vol. 29 Issue 5 Pg. 468-476 (Oct 01 2019) ISSN: 1952-4013 [Electronic] France
• PMID: 31789272 (Publication Type: Journal Article)

Chemical References

• CCR7 protein, human
• Cytokines
• GATA3 Transcription Factor
• GATA3 protein, human
• Receptors, CCR7
• STAT4 Transcription Factor
• STAT4 protein, human
• T-Box Domain Proteins
• T-box transcription factor TBX21
• Leukocyte Common Antigens
• PTPRC protein, human

Topics

• CD4-Positive T-Lymphocytes (immunology)
• CpG Islands (genetics)
• Cytokines (biosynthesis)
• DNA Methylation
• GATA3 Transcription Factor (genetics)
• Gene Expression
• Humans
• Leukocyte Common Antigens (immunology)
• Lymphopenia (immunology)
• Receptors, CCR7 (genetics)
• STAT4 Transcription Factor (genetics)
• Scleroderma, Systemic (genetics, immunology, metabolism)
• T-Box Domain Proteins (genetics)
• T-Lymphocytes, Regulatory (immunology)
• Th1 Cells (immunology)
• Th2 Cells (immunology)