Article

Opposing Effects of TGF-β and IL-15 Cytokines Control the Number of Short-Lived Effector CD8+ T Cells

Yale University School of Medicine, New Haven, CT 06520, USA.
Immunity (Impact Factor: 19.75). 08/2009; 31(1):131-44. DOI: 10.1016/j.immuni.2009.04.020
Source: PubMed

ABSTRACT An effective immune response against infectious agents involves massive expansion of CD8(+) T cells. Once the infection is cleared, the majority of these effector cells die through unknown mechanisms. How is expansion controlled to maximize pathogen clearance and minimize immunopathology? We found, after Listeria infection, plasma transforming growth factor beta (TGF-beta) titers increased concomitant with the expansion of effector CD8(+) T cells. Blocking TGF-beta signaling did not affect effector function of CD8(+) T cells. However, TGF-beta controlled effector cell number by lowering Bcl-2 amounts and selectively promoting the apoptosis of short-lived effector cells. TGF-beta-mediated apoptosis of this effector subpopulation occurred during clonal expansion and contraction, whereas interleukin-15 (IL-15) promoted their survival only during contraction. We demonstrate that the number of effector CD8(+) T cells is tightly controlled by multiple extrinsic signals throughout effector differentiation; this plasticity should be exploited during vaccine design and immunotherapy against tumors and autoimmune diseases.

Download full-text

Full-text

Available from: Richard A Flavell, Jul 02, 2015
0 Followers
 · 
108 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Regulation of an immune response requires complex crosstalk between cells of the innate and adaptive immune systems, via both cell-cell contact and secretion of cytokines. An important cytokine with a broad regulatory role in the immune system is transforming growth factor-β (TGF-β). TGF-β is produced by and has effects on many different cells of the immune system, and plays fundamental roles in the regulation of immune responses during homeostasis, infection and disease. Although many cells can produce TGFβ, it is always produced as an inactive complex that must be activated to bind to the TGFβ receptor complex and promote downstream signalling. Thus, regulation of TGFβ activation is a crucial step in controlling TGFβ function. This review will discuss how TGFβ controls diverse immune responses and how TGFβ function is regulated, with a focus on recent work highlighting a critical role for the integrin αvβ8 expressed by dendritic cells in activating TGFβ.
    Immunobiology 07/2012; 217(12). DOI:10.1016/j.imbio.2012.06.009 · 3.18 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: CD4⁺CD25⁺Foxp3⁺ T lymphocytes, known as regulatory T cells or T(regs), have been proposed to be a lineage of professional immune suppressive cells that exclusively counteract the effects of the immunoprotective "helper" and "cytotoxic" lineages of T lymphocytes. Here we discuss new concepts on the mechanisms and functions of T(regs). There are several key points we emphasize: 1. Tregs exert suppressive effects both directly on effector T cells and indirectly through antigen-presenting cells; 2. Regulation can occur through a novel mechanism of cytokine consumption to regulate as opposed to the usual mechanism of cytokine/chemokine production; 3. In cases where CD4⁺ effector T cells are directly inhibited by T(regs), it is chiefly through a mechanism of lymphokine withdrawal apoptosis leading to polyclonal deletion; and 4. Contrary to the current view, we discuss new evidence that T(regs), similar to other T-cells lineages, can promote protective immune responses in certain infectious contexts (Chen et al., 2011; Pandiyan et al., 2011). Although these points are at variance to varying degrees with the standard model of T(reg) behavior, we will recount developing findings that support these new concepts.
    Frontiers in Immunology 11/2011; 2:60. DOI:10.3389/fimmu.2011.00060
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Interleukin-2 receptor (IL-2R) signaling regulates tolerance and immunity. Here, we review recent work concerning the structure, signaling, and function of the IL-2R, emphasizing the contribution of IL-2 for T cell-dependent activity in vivo. IL-2R signaling influences two discrete aspects of immune responses by CD8(+) T cells, terminal differentiation of effector cells in primary responses, and aspects of memory recall responses. IL-2 also delivers essential signals for thymic development of regulatory T (Treg) cells and later to promote their homeostasis and function. Each of these outcomes on T effector and Treg cells requires distinct amounts of IL-2R signaling, with low IL-2R signaling sufficient for many key aspects of Treg cells. Thus, tolerance is readily maintained and favored with limited IL-2.
    Immunity 08/2010; 33(2):153-65. DOI:10.1016/j.immuni.2010.08.004 · 19.75 Impact Factor