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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI108891-01
Application #
8622024
Study Section
Special Emphasis Panel (ZAI1-LAR-I (S1))
Program Officer
Prabhudas, Mercy R
Project Start
2014-01-01
Project End
2018-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$429,942
Indirect Cost
$108,428
Name
Palo Alto Institute for Research & Edu, Inc.
Department
Type
DUNS #
624218814
City
Palo Alto
State
CA
Country
United States
Zip Code
94304
Wen, Zhenke; Shimojima, Yasuhiro; Shirai, Tsuyoshi et al. (2016) NADPH oxidase deficiency underlies dysfunction of aged CD8+ Tregs. J Clin Invest 126:1953-67
Li, Yinyin; Shen, Yi; Hohensinner, Philipp et al. (2016) Deficient Activity of the Nuclease MRE11A Induces T Cell Aging and Promotes Arthritogenic Effector Functions in Patients with Rheumatoid Arthritis. Immunity 45:903-916
Qi, Qian; Cavanagh, Mary M; Le Saux, Sabine et al. (2016) Diversification of the antigen-specific T cell receptor repertoire after varicella zoster vaccination. Sci Transl Med 8:332ra46
Yang, Zhen; Shen, Yi; Oishi, Hisashi et al. (2016) Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis. Sci Transl Med 8:331ra38
Watanabe, Ryu; Goronzy, Jörg J; Berry, Gerald et al. (2016) Giant Cell Arteritis: From Pathogenesis to Therapeutic Management. Curr Treatm Opt Rheumatol 2:126-137
Fang, Fengqin; Yu, Mingcan; Cavanagh, Mary M et al. (2016) Expression of CD39 on Activated T Cells Impairs their Survival in Older Individuals. Cell Rep 14:1218-31
Shirai, Tsuyoshi; Nazarewicz, Rafal R; Wallis, Barbara B et al. (2016) The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease. J Exp Med 213:337-54
Li, Guangjin; Ju, Jihang; Weyand, Cornelia M et al. (2015) Age-Associated Failure To Adjust Type I IFN Receptor Signaling Thresholds after T Cell Activation. J Immunol 195:865-74
Goronzy, Jörg J; Qi, Qian; Olshen, Richard A et al. (2015) High-throughput sequencing insights into T-cell receptor repertoire diversity in aging. Genome Med 7:117
Wang, Chen; Liu, Yi; Cavanagh, Mary M et al. (2015) B-cell repertoire responses to varicella-zoster vaccination in human identical twins. Proc Natl Acad Sci U S A 112:500-5

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