IL-15 Renders Conventional Lymphocytes Resistant to Suppressive Functions of Regulatory T Cells through Activation of the Phosphatidylinositol 3-Kinase Pathway

Abstract

International audienceIL-15 drives chronic inflammation in several human diseases. We have recently shown that IL-15 inhibits the immunosuppressive effects of TGF-beta through blockage of the Smad3-signaling pathway. Data pointing to reciprocal interactions between TGF-beta and CD4(+) regulatory T cells led us to investigate the impact of IL-15 on the de novo generation and function of regulatory T cells in humans. Our data indicate that IL-15 does not counteract, but rather promotes the effect of TGF-beta on the de novo generation of regulatory T cells (Treg). Thus, in the presence of TGF-beta, IL-15 enhanced the acquisition of regulatory functions by CD4(+)CD25(-) T cells stimulated by anti-CD3 and anti-CD28 Abs. In contrast, IL-15 impaired the functions of Tregs by acting on effector CD4 and CD8 T cells. Accordingly, in the presence of IL-15, proliferation and IFN-gamma production by peripheral CD4 and CD8 T cells could not be efficiently inhibited by Tregs. IL-15-induced resistance of effector T cells to Tregs resulted from activation of the PI3K signaling pathway but did not involve the rescue of effector T cells from apoptosis. Altogether, these data point to the ambiguous role of EL-15 in the control of Treg functions. This dual role may be instrumental to mount rapid but transient proinflammatory immune responses against pathogens but may become deleterious in situations associated with protracted IL-15 over-expression. The Journal of Immunology, 2009, 182: 6763-6770

Interleukin-15, a Master Piece in the Immunological Jigsaw of Celiac Disease

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IL-7 Abrogates Suppressive Activity of Human CD4+CD25+FOXP3+ Regulatory T Cells and Allows Expansion of Alloreactive and Autoreactive T Cells

“…Both IL-7 and IL-15 were shown to reverse suppression by Tregs (28,29). Moreover, it was reported that when IL-7 is used in combination with IL-2 for longterm expansion of Tregs, the expanded population showed increased proliferation and reduced suppressive capacity (30).…”

Astrocyte TLR4 activation induces a proinflammatory environment through the interplay between MyD88‐dependent NFκB signaling, MAPK, and Jak1/Stat1 pathways

“…IL-15 supports basal proliferation and survival of CD81 memory T cells (Sandau et al, 2010), and dual roles of IL-15 on the function of regulatory T cells (Treg) have been reported. Although IL-15 has the potential to promote regulatory T (Treg) cell function (Ben Ahmed et al, 2009;Xia et al, 2010), it can also have the opposite effects (Ben Ahmed et al, 2009). IL-15 can induce responses through a mechanism called trans-presentation (Stonier et al, 2010), suggesting a very local effect that depends on the cells and factors present in the surrounding microenvironment.…”