Declining immune function is well described in the elderly, and contributes significantly to increased risk and severity of infection, impaired responses to vaccination, and poorer control of cancer. Infections with several pathogens, whether viral (e.g., herpes viruses), bacterial (e.g., Mycobacteria) or parasitic (e.g., Leishmania), persist for the lifetime of the host. Reactivation of such persistent infections is a common consequence of waning immune function in the elderly. Regulatory T cells (Treg), a specialized subset of CD4+ T cells that have recently been shown to control the intensity of immune responses accumulate dramatically with age. While Treg negatively regulate immune responses, it is currently unclear whether their accumulation contributes negatively to immune function in the elderly. Our preliminary data in elderly humans and in a mouse model of Leishmania major infection show that Treg actively suppress the functionality oe found that aged Treg express increased levels of IL-7R1 and decreased levels of the pro-apoptotic molecule, Bim, and that expression of both of IL-7R1 and Bim are modulated by IL-2. Although IL-2 and IL-7 signaling can antagonize Bim-driven apoptosis, the underlying mechanisms remain unclear. Our data suggest that IL-7 drives cytosolic retention of FOXO3a, a major Bim transcriptional regulator, which may control Bim expression in aged Treg. Together, our data suggest a model in which chronic IL-2 signaling increases in vivo survival of Treg by enhancing IL-7-driven signals that lead to FOXO3a-dependent suppression of Bim expression. Two inter-related hypotheses: (i) age-dependent accumulation of Treg occurs through increased peripheral survival of Treg;(ii) Treg accumulation contributes directly to immune suppression in aging hosts, will be tested in experiments outlined in three Specific Aims. One, we will define the mechanisms of increased accumulation of Treg in aged animals. T is well described in the elderly, and contributes significatly to increased risk and severity of infection, impaired responses to vaccination, and poorer control of cancer. Mechanisms underlying declining immune function in the elderly remain unclear, but are critical to our ability to design innovative therapies. We have found that a """"""""suppressive"""""""" population of T cells accumulates in aging mice and humans. The proposal explores the mechanisms responsible for the accumulation of these suppressive cells and whether or not they can be manipulated to improve immune function in the aging.

Public Health Relevance

Declining immune function is well described in the elderly, and contributes significantly to increased risk and severity of infection, impaired responses to vaccination, and poorer control of cancer. Mechanisms underlying declining immune function in the elderly remain unclear, but are critical to our ability to design innovative therapies. We have found that a suppressive population of T cells accumulates in aging mice and humans. The proposal explores the mechanisms responsible for the accumulation of these suppressive cells and whether or not they can be manipulated to improve immune function in the aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
3R01AG033057-02S1
Application #
8326375
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Fuldner, Rebecca A
Project Start
2009-09-15
Project End
2012-08-31
Budget Start
2011-09-15
Budget End
2012-08-31
Support Year
2
Fiscal Year
2011
Total Cost
$99,844
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Almanan, Maha; Raynor, Jana; Sholl, Allyson et al. (2017) Tissue-specific control of latent CMV reactivation by regulatory T cells. PLoS Pathog 13:e1006507
Chougnet, Claire; Hildeman, David (2016) Helios-controller of Treg stability and function. Transl Cancer Res 5:S338-S341
Xin, Lijun; Jiang, Tony T; Kinder, Jeremy M et al. (2015) Infection susceptibility and immune senescence with advancing age replicated in accelerated aging Lmna(Dhe) mice. Aging Cell 14:1122-6
Chougnet, Claire A; Thacker, Robert I; Shehata, Hesham M et al. (2015) Loss of Phagocytic and Antigen Cross-Presenting Capacity in Aging Dendritic Cells Is Associated with Mitochondrial Dysfunction. J Immunol 195:2624-32
Kurtulus, S; Sholl, A; Toe, J et al. (2015) Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins. Cell Death Differ 22:174-84
Raynor, Jana; Karns, Rebekah; Almanan, Maha et al. (2015) IL-6 and ICOS Antagonize Bim and Promote Regulatory T Cell Accrual with Age. J Immunol 195:944-52
Shehata, Hesham M; Hoebe, Kasper; Chougnet, Claire A (2015) The aged nonhematopoietic environment impairs natural killer cell maturation and function. Aging Cell 14:191-9
Kurtulus, Sema; Hildeman, David (2013) Assessment of CD4(+) and CD8 (+) T cell responses using MHC class I and II tetramers. Methods Mol Biol 979:71-9
Tripathi, P; Koss, B; Opferman, J T et al. (2013) Mcl-1 antagonizes Bax/Bak to promote effector CD4(+) and CD8(+) T-cell responses. Cell Death Differ 20:998-1007
Raynor, Jana; Sholl, Allyson; Plas, David R et al. (2013) IL-15 Fosters Age-Driven Regulatory T Cell Accrual in the Face of Declining IL-2 Levels. Front Immunol 4:161

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