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: 21.56). 08/2009; 31(1):131-44. DOI: 10.1016/j.immuni.2009.04.020
Source: PubMed


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


Available from: Richard A Flavell
  • Source
    • "As influenza virus replicates primarily in epithelial tissue, the localization of CD8+ T cells adjacent to antigen may expose them to unique cytokines available in and near the epithelium such as TGF-β. TGF-β plays a role in both the contraction of effector T cells (69) and the establishment of TRM cells by inducing the expression of CD103 (70). The role of TGF-β in the development of TRM cells has been well described in the intestinal mucosa and the skin, and has also been implicated in the development of TRM in the lung (71). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Resident memory T cells (TRM) are broadly defined as a population of T cells, which persist in non-lymphoid sites long-term, do not re-enter the circulation, and are distinct from central memory T cells (TCM) and circulating effector memory T cells (TEM). Recent studies have described populations of TRM cells in the skin, gut, lungs, and nervous tissue. However, it is becoming increasingly clear that the specific environment in which the TRM reside can further refine their phenotypical and functional properties. Here, we focus on the TRM cells that develop following respiratory infection and reside in the lungs and the lung airways. Specifically, we will review recent studies that have described some of the requirements for establishment of TRM cells in these tissues, and the defining characteristics of TRM in the lungs and lung airways. With continual bombardment of the respiratory tract by both pathogenic and environmental antigens, dynamic fluctuations in the local milieu including homeostatic resources and niche restrictions can impact TRM longevity. Beyond a comprehensive characterization of lung TRM cells, special attention will be placed on studies, which have defined how the microenvironment of the lung influences memory T cell survival at this site. As memory T cell populations in the lung airways are requisite for protection yet wane numerically over time, developing a comprehensive picture of factors which may influence TRM development and persistence at these sites is important for improving T cell-based vaccine design.
    Full-text · Article · Jul 2014 · Frontiers in Immunology
  • Source
    • "In this study, Sanjabi et al. show that the number of effector CD8+ T cells following Listeria infection is under strict control of TGF-β and IL-15, which exerted contrasting effects during clonal expansion and contraction phases. While TGF-β supported apoptosis of effector CD8+ T cells, IL-15 maintained survival of CD8+ T cells during the contraction phase [54]. As mentioned above, in our present study we observed on one hand, that the level of TGF-β was significantly reduced in CIN 1 patients (consistent with the significant increase of systemic CD8+ T cells); while on the other hand, we also found an increase of IL-15 in this group, although this result was not significant. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The NKG2D receptor confers important activating signals to NK cells via ligands expressed during cellular stress and viral infection. This receptor has generated great interest because not only is it expressed on NK cells, but it is also seen in virtually all CD8+ cytotoxic T cells and is classically considered absent in CD4+ T cells. However, recent studies have identified a distinctive population of CD4+ T cells that do express NKG2D, which could represent a particular cytotoxic effector population involved in viral infections and chronic diseases. On the other hand, increased incidence of human papillomavirus-associated lesions in CD4+ T cell-immunocompromised individuals suggests that CD4+ T cells play a key role in controlling the viral infection. Therefore, this study was focused on identifying the frequency of NKG2D-expressing CD4+ T cells in patients with cervical intraepithelial neoplasia (CIN) 1. Additionally, factors influencing CD4+NKG2D+ T cell expansion were also measured. Close to 50% of patients with CIN 1 contained at least one of the 37 HPV types detected by our genotyping system. A tendency for increased CD4+ T cells and CD8+ T cells and decreased NK cells was found in CIN 1 patients. The percentage of circulating CD4+ T cells co-expressing the NKG2D receptor significantly increased in women with CIN 1 versus control group. Interestingly, the increase of CD4+NKG2D+ T cells was seen in patients with CIN 1, despite the overall levels of CD4+ T cells did not significantly increase. We also found a significant increase of soluble MICB in CIN 1 patients; however, no correlation with the presence of CD4+NKG2D+ T cells was seen. While TGF-beta was significantly decreased in the group of CIN 1 patients, both TNF-alpha and IL-15 showed a tendency to increase in this group. Taken together, our results suggest that the significant increase within the CD4+NKG2D+ T cell population in CIN 1 patients might be the result of a chronic exposure to viral and/or pro-inflammatory factors, and concomitantly might also influence the clearance of CIN 1-type lesion.
    Full-text · Article · Aug 2013 · Journal of Biomedical Science
  • Source
    • "TGF-β can both positively and negatively regulate numerous immune populations, with inhibitory effects on Th1 and Th2 differentiation and positive effects on Treg and Th17 development [6], [7]. In addition, TGF-β has been reported to protect T cells from induction of apoptosis, in certain situations [8], [9], [10]. Complete loss of TGF-β RII or TGF-β1 leads to massive dysregulation in T cell homeostasis and fatal autoimmunity, mediated in part by loss of regulatory T cells [4], [11]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The pleiotropic cytokine TGF-β has been implicated in the regulation of numerous aspects of the immune response, including naïve T cell homeostasis. Previous studies found that impairing TGF-β responsiveness (through expression of a dominant-negative TGF-β RII [DNRII] transgene) leads to accumulation of memory phenotype CD8 T cells, and it was proposed that this resulted from enhanced IL-15 sensitivity. Here we show naïve DNRII CD8 T cells exhibit enhanced lymphopenia-driven proliferation and generation of "homeostatic" memory cells. However, this enhanced response occurred in the absence of IL-15 and, unexpectedly, even in the combined absence of IL-7 and IL-15, which were thought essential for CD8 T cell homeostatic expansion. DNRII transgenic CD8 T cells still require access to self Class I MHC for homeostatic proliferation, arguing against generalized dysregulation of homeostatic cues. These findings suggest TGF-β responsiveness is critical for enforcing sensitivity to homeostatic cytokines that limit maintenance and composition of the CD8 T cell pool. (154 words).
    Full-text · Article · Aug 2012 · PLoS ONE
Show more