Double-Edged Sword: Interleukin-2 Promotes T Regulatory Cell Differentiation but Also Expands Interleukin-13- and Interferon-γ-Producing CD8+ T Cells via STAT6-GATA-3 Axis in Systemic Lupus Erythematosus

• Published in: Frontiers in immunology Vol. 12; p. 635531
• Main Authors: Kato, Hiroshi, Perl, Andras
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 02.03.2021
• Subjects: Adult; Case-Control Studies; CD8+ T cells; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Differentiation - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Female; GATA3 Transcription Factor - metabolism; Humans; Immunology; Interferon-gamma - metabolism; interferon-γ (IFN-γ); interleukin-13 (IL-13); Interleukin-13 - metabolism; interleukin-2 (IL-2); Interleukin-2 - pharmacology; Interleukin-2 - toxicity; Lupus Erythematosus, Systemic - diagnosis; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - metabolism; Lymphocyte Activation - drug effects; Male; Middle Aged; Phenotype; Phosphorylation; Signal Transduction; STAT6 Transcription Factor - metabolism; systemic lupus erythematosus; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T regulatory (Treg) cell; interleukin-13 (IL-13); CD8+ T cells; systemic lupus erythematosus; interleukin-2 (IL-2); STAT6; T regulatory (Treg) cell; interferon-γ (IFN-γ); GATA-3
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.635531

Interleukin-2 (IL-2) expands the depleted T regulatory (Treg) cell population, and it has emerged as a potential therapy in systemic lupus erythematosus (SLE). However, IL-2 administration may involve the risk of expanding unwanted pro-inflammatory cells. We herein studied the effects of IL-2 on pro-inflammatory cytokine production by CD4 + and CD8 + T cells in parallel with Treg development following CD3/CD28 co-stimulation. While Treg cells are depleted in SLE patients, their CD4 + T cells were poised to receive and activate IL-2 signaling as evidenced by upregulation of CD25 and enhanced IL-2-incued STAT5 phosphorylation during Treg differentiation. In patients with SLE, however, IL-2 also expanded CD8 + T cells capable of producing interleukin-5, interkeukin-13 (IL-13), and interferon-γ (IFN-γ) that occurred with enhanced expression of GATA-3 and phosphorylation of STAT6 but not STAT5. Our data pinpoint a safety signal for systemic administration of IL-2 and challenges a long-held conceptual platform of type 1 and 2 cytokine antagonism by newly documenting the IL-2-dependent development of IL-13 and IFN-γ double-positive (IL-13 + IFNγ + ) CD8 + T cells in SLE.