Phosphorylation and coupling of ζ-chains to activated T-cell receptor (TCR)/CD3 complexes from peripheral blood T-cells of elderly humans

Whisler, Ronald L.; Karanfilov, Chris I; Newhouse, Yvonne G.; Fox, Charity C.; Lakshmanan, Romola R.; Beiqing, Liu

doi:10.1016/s0047-6374(98)00084-0

Cited by 24 publications

(8 citation statements)

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“…Previous studies have clearly demonstrated that aging is accompanied by deficits in activation-induced T cell responses such as of IL-2R expression, IL-2 secretion and proliferation [1][2][3][4][5][6][7][8]. We have previously demonstrated that decreased induction of the transcription factor NFκB, contributes to lowered induction of IL-2R during aging [4,9].…”

Section: Introductionmentioning

confidence: 85%

Redox regulation of the proteasome in T lymphocytes during aging

Das

Ponnappan

2007

Free Radical Biology and Medicine

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Proteasome is a major cellular organelle responsible for the regulated turn-over of both normal and misfolded proteins. Recent reports from our laboratory have implicated lowered proteasomal chymotryptic activity to be responsible for decreased induction of the transcription factor NFκB in T lymphocytes during aging. In this study, we have further analyzed the basis for this decline in proteasomal function, by focusing on the role of oxidative stress. Upon exposure to the pro-oxidant BSO, both ATP-stimulatable 26S, as well as ATP-independent 20S proteasomal catalytic activity could be down-regulated in T cells from young donors, mimicking the decline observed in T cells from the elderly. Loss in these catalytic activities, following exposure to pro-oxidant stimulus also resulted in a decline in both activation-induced proliferation as well as degradation of the inhibitor IκBα, with concomitant increase in the accumulation of carbonylated proteins, mimicking responses seen in T cells from the elderly. Pretreatment with an antioxidant, NAC could override pro-oxidantmediated, but not age-associated decrease in both 20S proteasomal activities. These results suggest that the decrease in proteasomal activities observed during aging may be secondary to oxidative stress and underlie immune senescence.

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Section: Introductionmentioning

confidence: 85%

Redox regulation of the proteasome in T lymphocytes during aging

Das

Ponnappan

2007

Free Radical Biology and Medicine

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“…As already mentioned, the first step in TCR-mediated signal transduction is the activation of different tyrosine kinases, leading to the tyrosine phosphorylation of several downstream proteins [61,62]. Several signalling pathways were found altered with ageing either in experimental animals or in humans.…”

Section: Tcr and Costimulatory Signalling Changes With Ageing: A Biocmentioning

confidence: 99%

Ageing, autoimmunity and arthritis: Perturbations of TCR signal transduction pathways with ageing – a biochemical paradigm for the ageing immune system

et al. 2003

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290 APC = antigen-presenting cell; DRM = detergent-resistant microdomain; ERK = extracellular signal-regulated kinase; IFN = interferon; IL = interleukin; ITAM = immunoreceptor tyrosine-based activation motif; LAT = linker of activated T cells; mAb = monoclonal antibody; MAPK = mitogenactivated protein kinase; MHC = major histocompatibility complex; NF = nuclear factor; NFAT = nuclear factor of activated T cells; PKC = protein kinase C; pLAT, tyrosine-phosphorylated LAT; PTK = protein tyrosine kinase; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; TCR = T-cell receptor; Th cells = T helper cells; ZAP = zeta-associated protein. Arthritis Research & TherapyVol 5 No 6 Fülöp et al. IntroductionIt is widely accepted that cell-mediated immune functions (cytotoxicity, delayed-type hypersensitivity, etc.) decline with age [1,2]. These age-associated immunological changes render an individual more susceptible to infection and possibly cancer, as well as to age-associated autoimmune disorders; they may also contribute to atherosclerosis and Alzheimer's disease [3][4][5]. There is still no clear consensus as to why cell-mediated immunity declines with age. It is generally believed that age-related immune deficiency develops coincident with the gradual involution of the thymus gland and, consequently, that thymic-related (T-cell) functions are the most profoundly affected. It has recently been suggested that the alterations observed with ageing are a reflection of an accumulation of relatively inert memory T cells and a consequent AbstractIt is widely accepted that cell-mediated immune functions decline with age, rendering an individual more susceptible to infection and possibly cancer, as well as to age-associated autoimmune diseases. The exact causes of T-cell functional decline are not known. One possible cause could be the development of defects in the transduction of mitogenic signals following TCR stimulation. This T-cell hyporesponsiveness due to defects of signalling through the TCR either from healthy elderly subjects or from individuals with autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus results in an impaired ability to mount efficient immune responses and to maintain responsiveness to foreign antigens. This implies that a high proportion of autoreactive T cells might accumulate either intrathymically or in the periphery. T-cell anergy and differential TCR signalling could thus also be key players in the disruption of tolerance and the onset of autoimmune diseases. The increasing number of the elderly may lead to an increase of clinically important autoimmune diseases. We will review the signal transduction changes through the TCR-CD3 complex in T lymphocytes from healthy elderly subjects, which result in a modification of the activation of transcription factors involved in IL-2 gene expression leading to decreased IL-2 production. The putative contribution of altered T-cell signalling with ageing in the development of autoimmune diseases will be also discussed.

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“…The adverse sequelae of immunosenescence reflect underlying physiologic shifts in signal transduction. These changes include increased pro‐inflammatory cytokines, less diversity in T‐cell antigen recognition, and impaired T‐cell proliferation 4–9 . Specific aging‐associated changes include lower levels of the T‐cell receptor‐CD3 complex 4,7,10 and decreased proliferation and secretion of IL‐2 11,12 .…”

Section: Introductionmentioning

confidence: 99%

“…These changes include increased pro‐inflammatory cytokines, less diversity in T‐cell antigen recognition, and impaired T‐cell proliferation 4–9 . Specific aging‐associated changes include lower levels of the T‐cell receptor‐CD3 complex 4,7,10 and decreased proliferation and secretion of IL‐2 11,12 . Our lab has previously demonstrated that immunosenescence‐associated diminished CD3 zeta and IL‐2 levels as well as decreased downstream expression of Janus kinases (JAK‐2 and JAK‐3) may result in women arising out of menopausal hypo‐estrogenic conditions.…”

Section: Introductionmentioning

confidence: 99%