The reduced ability of the aging immune system to mount adaptive immune responses compromises the efficacy of vaccinations and increases the morbidity from infections. Adaptive immune responses to exogenous or endogenous threats rely on a diverse T cell repertoire and the rapid activation and expansion of an antigen-specific T cell population and acquisition of effector functions. In studying the effect of age on CD4 T cell function, we have identified a decline in miR181a as a characteristic hallmark of T cell aging. Our studies so far have focused on the dual-specific phosphatase (DUSP) 6 which is repressed by miR181a and therefore reciprocally increases with age. DUSP6 calibrates the T cell receptor activation threshold at which stimulation is translated into a productive signal. Increased DUSP6 contributes to the lowered sensitivity of elderly T cells to respond. miRNAs function by repressing the translation of sets of genes, frequently belonging to related pathways. The current proposal is based on the hypothesis that the decline in miR181a and the co-regulated miR181b is of broad importance to understand T cell aging and has consequences that go beyond increased DUSP6 activity. In addition to DUSP6, we will focus on SIRT1, BCL-2, and TCL1. What DUSP6 and SIRT1 have in common is that they control negative feedback loops in T cell activation. SIRT1, BCL-2 and TCL1 are critical components of T cell survival pathways. The decline in miR181a/b therefore results in a T cell phenotype that favors cellular longevity and quiescence at the expense of activation and effector function.
In Aim 1, we will examine the epigenetic, transcriptional and post-transcriptional mechanisms that control miR181a/b expression. The objectives of these studies are to understand what drives the decline in miR181a/b with age and to identify means to upregulate expression.
Aim 2 will examine the influence of age on the expression of SIRT1, BCL-2, and TCL1 in T cell subsets and determine whether age-related changes in protein expression are caused by the degree of miR181a/b expression and can be reversed by miR181a/b overexpression.
In Aim 3, we will examine the functional consequences of miR181a/b loss, and we will determine whether they can be attributed to the overexpression of DUSP6, SIRT1, TCL1 or BCL-2.
With increasing age, the ability of the immune system to fend off infectious organisms or to control chronic infections declines. Consequences include the age-dependent reactivation of zoster infections, the increased morbidity and mortality from influenza, and the reduced response to vaccinations. With the changing demographics of the US population, this age-related immune incompetence is a major health problem. We hypothesize that a decline in miR181a with age leads to the increased expression of several molecules including DUSP6 and SIRT1 that dampen T cell responses and lead to the accumulation of senescent T cells.
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| Zhang, Hui; Watanabe, Ryu; Berry, Gerald J et al. (2018) Inhibition of JAK-STAT Signaling Suppresses Pathogenic Immune Responses in Medium and Large Vessel Vasculitis. Circulation 137:1934-1948 |
| Li, Yinyin; Goronzy, Jörg J; Weyand, Cornelia M (2018) DNA damage, metabolism and aging in pro-inflammatory T cells: Rheumatoid arthritis as a model system. Exp Gerontol 105:118-127 |
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| Watanabe, Ryu; Maeda, Toshihisa; Zhang, Hui et al. (2018) MMP (Matrix Metalloprotease)-9-Producing Monocytes Enable T Cells to Invade the Vessel Wall and Cause Vasculitis. Circ Res 123:700-715 |
| Weyand, Cornelia M; Shen, Yi; Goronzy, Jorg J (2018) Redox-sensitive signaling in inflammatory T cells and in autoimmune disease. Free Radic Biol Med 125:36-43 |
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| Goronzy, Jörg J; Weyand, Cornelia M (2017) Successful and Maladaptive T Cell Aging. Immunity 46:364-378 |
| Zhang, Hui; Watanabe, Ryu; Berry, Gerald J et al. (2017) Immunoinhibitory checkpoint deficiency in medium and large vessel vasculitis. Proc Natl Acad Sci U S A 114:E970-E979 |
| Wen, Zhenke; Shen, Yi; Berry, Gerald et al. (2017) The microvascular niche instructs T cells in large vessel vasculitis via the VEGF-Jagged1-Notch pathway. Sci Transl Med 9: |
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