Functional properties of CD4+CD28− T cells in the aging immune system

Weyand, Cornelia M.; Brandes, Johann C.; Schmidt, Dorle; Fulbright, James W.; Goronzy, Jörg J.

doi:10.1016/s0047-6374(97)00161-9

Cited by 176 publications

(124 citation statements)

References 46 publications

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“…Data shown are representative of two independent experiments involving triplicate concurrent transfections. null T cells fail to express CD40 ligand and are unable to support B cell proliferation and immunoglobulin production in vitro (22). This corroborates previous studies that demonstrated the requirement of CD28 in T cell-dependent B cell-mediated immune responses (43).…”

Section: Accumulation Of Cd4ϩcd28 Null T Cells In An Agingsupporting

confidence: 89%

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Aging-related Deficiency of CD28 Expression in CD4+ T Cells Is Associated with the Loss of Gene-specific Nuclear Factor Binding Activity

Vallejo

Nestel²,

Schirmer³

et al. 1998

Journal of Biological Chemistry

164

179

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Changes in T cell populations and concomitant perturbation of T cell effector functions have been postulated to account for many aging-related immune dysfunctions. Here, we report that high frequencies of CD28 null CD4؉ T cells were found in elderly individuals. Because deviations in the function of these unusual CD4؉ T cells might be directly related to CD28 deficiency, we examined the molecular basis for the loss of CD28 expression in CD4؉ T cells. In reporter gene bioassays, the minimal promoter of the CD28 gene was mapped to the proximal 400 base pairs (bp) of the 5 untranslated region. CD28 deficiency was associated with the loss of two noncompeting binding activities within a 67-bp segment of the minimal promoter. These binding activities were not competed by consensus Ets, Elk, or AP3 motifs that were found within the sequence stretch. The DNA-protein complexes were also not recognized by antibodies to Ets-related transcription factors. Furthermore, introduction of mutations into the 67-bp segment at positions corresponding to the two DNA-protein interaction sites, i.e. nucleotides spanning ؊206 to ؊179 and ؊171 to ؊148, resulted in the loss of specific nuclear factor binding activities and the abrogation of promoter activity. These observations implicate at least two regulatory motifs in the constitutive expression of CD28. The loss of binding activity of transacting factors specific for these sequences may contribute to the accumulation CD4؉CD28 null T cells during aging.

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Section: Accumulation Of Cd4ϩcd28 Null T Cells In An Agingsupporting

confidence: 89%

“…Consistent with this hypothesis are the features of these cells, namely, their in vivo clonality and longevity, memory phenotype, and unusual functional profiles, including defective B cell help activity (17)(18)(19)(20)(21)(22). All of these characteristics are considered to be hallmarks of an aging immune system (1).…”

mentioning

confidence: 79%

Aging-related Deficiency of CD28 Expression in CD4+ T Cells Is Associated with the Loss of Gene-specific Nuclear Factor Binding Activity

Vallejo

Nestel²,

Schirmer³

et al. 1998

Journal of Biological Chemistry

164

179

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“…We found that expression of the costimulatory molecules CTLA4 and PD-1 did not differ with respect to age in CD4 memory cells, a finding which mirrored Fann et al's results with respect to senescence phenotype in CD8 T cells. While CD40L is significantly downregulated in CD8 + CD28 − T cells [33], we did not detect an age-dependent decline in memory CD4 cells; however, we have previously shown that CD28 − CD4 + T cells lack the ability to induce CD40L [34]. Furthermore, there are many similarities in the expression of NK cell receptors on CD28 − CD8 and CD4 T cells.…”

Section: Age-dependent Changes In the Transcriptional Profile Of Cd4 contrasting

confidence: 73%

T cell subset-specific susceptibility to aging

Cześnikiewicz-Guzik

Lee

Cui

et al. 2008

Clinical Immunology

379

335

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With increasing age, the competence of the immune system to fight infections and tumors declines. Age-dependent changes have been mostly described for human CD8 T cells, raising the question of whether the response patterns for CD4 T cells are different. Gene expression arrays of memory CD4 T cells yielded a similar age-induced fingerprint as has been described for CD8 T cells. In crosssectional studies, the phenotypic changes were not qualitatively different for CD4 and CD8 T cells, but occurred much more frequently in CD8 T cells. Homeostatic stability partially explained this lesser age sensitivity of CD4 T cells. With aging, naïve and central memory CD8 T cells were lost at the expense of phenotypically distinct CD8 effector T cells, while effector CD4 T cells did not accumulate. However, phenotypic shifts on central memory T cells were also more pronounced in CD8 T cells. This distinct stability in cell surface marker expression can be reproduced in vitro. The data show that CD8 T cells are age sensitive by at least two partially independent mechanisms: fragile homeostatic control and gene expression instability in a large set of regulatory cell surface molecules.

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“…Suggestive evidence shows that CD8 ϩ CD28 null T cells show suppressive capacity in a mouse model of RA (12,13). However, CD4 ϩ CD28 null T cells are incapable of providing B cell help, show cytolytic activity, and produce high levels of IL-2 and IFN-␥, giving them the ability to function as proinflammatory cells (7,14,15). Thus, they likely contribute to and stabilize the Th1 response, which is the underlying immunological process driving immunopathologies such as of RA.…”

mentioning

confidence: 99%

Surface CD152 (CTLA-4) Expression and Signaling Dictates Longevity of CD28null T Cells

Hoff

Knieke²,

Cabail³

et al. 2009

The Journal of Immunology

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CD28null T cells are a highly enriched subset of proinflammatory T cells in patients with autoimmune diseases that are oligoclonal and autoreactive. In this study, we analyzed the role of CD152 signaling on the longevity of human CD28null T cells. Using a sensitive staining method for CD152, we show that human CD4+CD28null and CD8+CD28null T cells rapidly express surface CD152. Serological inactivation of CD152 using specific Fab or blockade of CD152 ligands using CTLA-4Ig in CD4+CD28null and CD8+CD28null T cells enhances apoptosis in a Fas/FasL-dependent manner. CD152 cross-linking on activated CD28null cells prevents activation-induced cell death as a result of reduced caspase activity. Apoptosis protection conferred by CD152 is mediated by phosphatidylinositol 3′-kinase-dependent activation of the kinase Akt, resulting in enhanced phosphorylation and thereby inhibition of the proapoptotic molecule Bad. We show that signals triggered by CD152 act directly on activated CD28null T lymphocytes and, due to its exclusive expression as a receptor for CD80/CD86 on CD28null T cells, prevention of CD152-mediated signaling is likely a target mechanism taking place during therapy with CTLA-4Ig. Our data imply strongly that antagonistic approaches using CD152 signals for chronic immune responses might be beneficial.

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Functional properties of CD4+CD28− T cells in the aging immune system

Cited by 176 publications

References 46 publications

Aging-related Deficiency of CD28 Expression in CD4+ T Cells Is Associated with the Loss of Gene-specific Nuclear Factor Binding Activity

Aging-related Deficiency of CD28 Expression in CD4+ T Cells Is Associated with the Loss of Gene-specific Nuclear Factor Binding Activity

T cell subset-specific susceptibility to aging

Surface CD152 (CTLA-4) Expression and Signaling Dictates Longevity of CD28null T Cells

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