Age-related defects in the cytoskeleton signaling pathways of CD4 T cells

Garcia, Gonzalo G.; Miller, Richard A.

doi:10.1016/j.arr.2009.11.003

Cited by 28 publications

(28 citation statements)

References 151 publications

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“…As previously discussed, class switch recombination is impaired in aging murine and human B cells due to decreased expression of enzymes such as AID (53,84). Aberrant T cell signaling has also been associated with aging (48,85), and the list of dysregulated genes continues to grow, as indicated by several recent reports (86)(87)(88), two of which focused on altered expression of dual specific phosphatases (DUSPs). DUSPs deactivate target kinases, including those in the MAPK pathway whose activity is critical for T cell activation, differentiation, and cytokine production.…”

Section: Intracellular Changes In Developing and Mature Lymphocytesmentioning

confidence: 87%

Causes, consequences, and reversal of immune system aging

Montecino‐Rodriguez

Berent-Maoz²,

Dorshkind³

2013

J. Clin. Invest.

648

464

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The effects of aging on the immune system are manifest at multiple levels that include reduced production of B and T cells in bone marrow and thymus and diminished function of mature lymphocytes in secondary lymphoid tissues. As a result, elderly individuals do not respond to immune challenge as robustly as the young. An important goal of aging research is to define the cellular changes that occur in the immune system and the molecular events that underlie them. Considerable progress has been made in this regard, and this information has provided the rationale for clinical trials to rejuvenate the aging immune system.

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Section: Intracellular Changes In Developing and Mature Lymphocytesmentioning

confidence: 87%

Causes, consequences, and reversal of immune system aging

Montecino‐Rodriguez

Berent-Maoz²,

Dorshkind³

2013

J. Clin. Invest.

648

464

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“…However, the functional consequences of elevated TORC1 and TORC2 activity and their roles in aging remain unknown (52), with the exception of the association with cancer (53). We have previously shown that CD4 T lymphocytes exhibit alterations in the cytoskeleton, in TCR signaling, and in immune synapse formation that are associated with decreased pERM expression (29) and defects in CD28 signaling (32). Other investigators have reported declines in BIM expression (33).…”

Section: Discussionmentioning

confidence: 99%

“…These alterations include cytoskeletal changes and declines in TCR dependent activation (25–29), increased cell size (27), altered RhoA and Rac activity (30), decreased pERM (558) expression (30), and decreased proliferation in vivo (31). We recently demonstrated that some of these defects are the result of alterations in TCR/CD28 signaling (32).…”

Section: Introductionmentioning

confidence: 99%

Increased Mammalian Target of Rapamycin Complex 2 Signaling Promotes Age-Related Decline in CD4 T Cell Signaling and Function

Perkey

Fingar

Miller

et al. 2013

The Journal of Immunology

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CD4 T cell function declines significantly during aging. While the mammalian target of rapamycin (TOR) has been implicated in aging, the roles of the TOR complexes (TORC1, TORC2) in the functional declines of CD4 T cells remain unknown. In this study, we demonstrate that aging increases TORC2 signaling in murine CD4 T cells, a change blocked by long-term exposure to rapamycin, suggesting that functional defects may be the result of enhanced TORC2 function. Using overexpression of Rheb to activate TORC1 and Rictor plus Sin1 to augment TORC2 in naïve CD4 T cells from young mice, we demonstrated that increased TORC2, but not TORC1, signaling results in aging-associated biochemical changes. Furthermore, elevated TORC2 signaling in naïve CD4 T cells from young mice leads to in vivo functional declines. The data presented herein suggest a novel model in which aging increases TORC2 signaling and leads to CD4 T cell defects in old mice.

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“…It is unclear whether these changes in cytokine production are associated with L-deprenyl-induced alterations in the populations of T-helper, T-cytotoxic, and T-regulatory lymphocytes but the improvement in cytokine production may have been due to the release of NE by the newly established NA nerve fibers in the spleen as it is an important signal molecule for T cell functions in spleen and lymph nodes [22]. Age-related lymphoproliferative responses in the spleens of female rats were not altered by L-deprenyl treatment indicating that it is unable to reverse the age-associated decline in immunological synapse formation due to impaired cytoskeletal signaling pathways and also, the expression of costimulatory molecule, CD28, on T cells [23, 24]. These impaired signaling pathways and down-regulated expression of major costimulatory molecules such as CD28 in T cells may have been responsible for similar lack of effect of L-deprenyl treatment on T cell proliferation in the spleens of young and old male rats and tumor-bearing female rats [2, 11–13].…”

Section: Discussionmentioning

confidence: 99%

<smlcap>l</smlcap>-Deprenyl Reverses Age-Associated Decline in Splenic Norepinephrine, Interleukin-2 and Interferon-γ Production in Old Female F344 Rats

ThyagaRajan

Madden

Boehm

et al. 2012

Neuroimmunomodulation

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Aging in female rats is associated with cessation of reproductive cycles, development of mammary cancer, and increased incidence of autoimmune diseases. Previously, we demonstrated an age-related decline in sympathetic noradrenergic (NA) innervation in the spleen and lymph nodes of female F344 rats accompanied by significantly reduced natural killer cell activity, interleukin (IL)-2 and interferon (IFN)-γ production, and T- and B-cell proliferation, suggesting possible links between sympathetic activity and immunosenescence. Objectives: The aim of this study is to investigate the effects of l-(–)-deprenyl, a monoamine oxidase-B inhibitor, on the sympathetic nervous system and cell-mediated immune responses in old female rats. Methods: Low doses of l-deprenyl (0.25 or 1.0 mg/kg body weight, BW) were administered intraperitoneally to 19- to 21-month-old female F344 rats for 8 weeks. To assess the stereoselectivity of the effects of deprenyl on splenic sympathetic activity and immune responses, the d-enantiomer (d-(+)-deprenyl; 1.0 mg/kg BW) was also included in the studies. Norepinephrine (NE) concentration and content, and mitogen-induced T-cell proliferation and cytokine production were assessed in the splenocytes after deprenyl treatment. Results: Treatment with l-deprenyl reversed the age-related decrease in NE concentration and content and IFN-γ production, and increased IL-2 production in the spleen while d-deprenyl did not affect the age-associated reduction in splenic NE levels or cytokine production. Conclusions: These findings demonstrate that l-deprenyl exerts neurorestorative and immunostimulatory effects on the sympathetic nervous system and cell-mediated immune responses during aging and provides evidence for a causal relationship between some aspects of immunosenescence and the age-related decline in sympathetic nerves in the spleens of female F344 rats.

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Age-related defects in the cytoskeleton signaling pathways of CD4 T cells

Cited by 28 publications

References 151 publications

Causes, consequences, and reversal of immune system aging

Causes, consequences, and reversal of immune system aging

Increased Mammalian Target of Rapamycin Complex 2 Signaling Promotes Age-Related Decline in CD4 T Cell Signaling and Function

<smlcap>l</smlcap>-Deprenyl Reverses Age-Associated Decline in Splenic Norepinephrine, Interleukin-2 and Interferon-γ Production in Old Female F344 Rats

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