Journal Article

IL-15 augments TCR-induced CD4+ T cell expansion in vitro by inhibiting the suppressive function of CD25 High CD4+ T cells

Grooten, Johan, Wei, Xiao-Qing, Boonefaes, Tom, Dooms, Hans, Leclercq, Georges, Van Belle, Tom L

2012

Overview

Due to its critical role in NK cell differentiation and CD8(+) T cell homeostasis, the importance of IL-15 is more firmly established for cytolytic effectors of the immune system than for CD4(+) T cells. The increased levels of IL-15 found in several CD4(+) T cell-driven (auto-) immune diseases prompted us to examine how IL-15 influences murine CD4(+) T cell responses to low dose TCR-stimulation in vitro. We show that IL-15 exerts growth factor activity on both CD4(+) and CD8(+) T cells in a TCR-dependent and Cyclosporin A-sensitive manner. In CD4(+) T cells, IL-15 augmented initial IL-2-dependent expansion and once IL-15Rα was upregulated, IL-15 sustained the TCR-induced expression of IL-2/15Rβ, supporting proliferation independently of secreted IL-2. Moreover, IL-15 counteracts CD4(+) T cell suppression by a gradually expanding CD25(High)CD4(+) T cell subset that expresses Foxp3 and originates from CD4(+)CD25(+) Tregs. These in vitro data suggest that IL-15 may dramatically strengthen the T cell response to suboptimal TCR-triggering by overcoming an activation threshold set by Treg that might create a risk for autoimmune pathology.

• Publisher: Public Library of Science (PLoS)
• Subject: Animals / Antigens, CD - genetics / Antigens, CD - immunology / CD4-Positive T-Lymphocytes - cytology / CD4-Positive T-Lymphocytes - drug effects / CD4-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - cytology / CD8-Positive T-Lymphocytes - drug effects / CD8-Positive T-Lymphocytes - immunology / Cell Proliferation - drug effects / Cells, Cultured / Cyclosporine - pharmacology / Flow Cytometry / Forkhead Transcription Factors - genetics / Forkhead Transcription Factors - immunology / Gene Expression Regulation - drug effects / Gene Expression Regulation - immunology / Humans / Immune Tolerance / Interleukin-15 - immunology / Interleukin-15 - pharmacology / Interleukin-15 Receptor alpha Subunit - genetics / Interleukin-15 Receptor alpha Subunit - immunology / Interleukin-2 - biosynthesis / Interleukin-2 - secretion / Interleukin-2 Receptor beta Subunit - genetics / Interleukin-2 Receptor beta Subunit - immunology / Lymphocyte Activation - drug effects / Mice / Receptors, Antigen, T-Cell - immunology / Receptors, Antigen, T-Cell - metabolism / Signal Transduction - drug effects / T-Lymphocytes, Regulatory - cytology / T-Lymphocytes, Regulatory - drug effects / T-Lymphocytes, Regulatory - immunology