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 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 of effector T cells. Our preliminary data also show that Treg depletion increases aged human cytomegalovirus (CMV)-specific T cell responses in vitro. In addition, in murine CMV (MCMV)- infected young mice, Treg depletion significantly increased MCMV-specific T cell responses in vivo. Although Treg likely contribute to immunosuppression with age, the mechanisms underlying Treg accumulation in the elderly remain unclear. Our preliminary data suggest that Treg accumulation in mice is progressive and is caused by their increased resistance to apoptosis. More specifically, we found that (i) levels o the pro-apoptotic molecule Bim in Treg are normally and progressively decreased with age;(ii) in the absence of Bim, Treg accumulate faster;(iii) IL-2 and IL-15 play a partially redundant role in driving Treg accrual in aged mice;(iv) the additional loss of Bim restores the loss of Treg in aged IL-15-deficient mice;(v) acute, in vivo loss of forkhead box transcription factor subclass O (FOXO) members 1, 3a, and 4 lead to decreased expression of Bim in Treg . Together, our data suggest a model in which chronic cytokine signaling increases in vivo survival of Treg by enhancing FOXO3a-dependent suppression of Bim-expression. Our overarching hypothesis is that accrual of Treg in aged mice and humans are due to cytokine-driven repression of Bim expression and contributes to immunosuppression and pathogen persistence. This hypothesis will be tested in three Specific Aims: (1): Define the mechanisms of increased accumulation of Treg in aged hosts;(2) Define the homeostasis and functionality of Treg in two models of persistent infection, Leishmania major and MCMV;(3) Determine if a Bim/FOXO axis controls Treg survival in humans and the role of Treg in dampening CMV-specific T cell responses in elderly humans. The long-term aim of this research is to determine the role of Treg in the immune suppression of aging, and to devise novel therapeutic approaches to enhance infection control as well as vaccine efficacy in the elderly.
Declining immune function is a hallmark of normal aging and contributes significantly to decreased vaccine efficacy and reactivation of persistent infections i the elderly. Thus, new strategies aimed at restoring immune function in aged humans could have dramatic benefits to human health. In both humans and mice, we have found that a population of suppressive immune cells accumulates with age. In this proposal, we will study mechanisms that promote the accrual of these suppressive cells. Further, we will test strategies that promote the elimination of these cells and study the effects of these strategies on the outcome of persistent infection.
|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|
|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|
|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|
|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|
|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|
|Pierson, Wim; Cauwe, Bénédicte; Policheni, Antonia et al. (2013) Antiapoptotic Mcl-1 is critical for the survival and niche-filling capacity of Foxp3? regulatory T cells. Nat Immunol 14:959-65|
|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|
|Raynor, Jana; Lages, Celine S; Shehata, Hesham et al. (2012) Homeostasis and function of regulatory T cells in aging. Curr Opin Immunol 24:482-7|
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