Cell Surface CD28 Levels Define Four CD4+ T Cell Subsets: Abnormal Expression in Rheumatoid Arthritis

Salazar-Fontana, Laura-Inés; Sanz, Eva; Mérida, Isabel; Zea, Antonio; Sánchez-Atrio, Ana; Villa, L. F.; Martı́nez-A, Carlos; Hera, Alberto De La; Álvarez‐Mon, Melchor

doi:10.1006/clim.2001.5003

Cited by 31 publications

(32 citation statements)

References 57 publications

(70 reference statements)

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“…The data presented here show that a high frequency of CD4ϩ,CD28-null T cells is characteristic of patients with extraarticular RA (Figure 2), which is consistent with findings of previous studies (8,9). Patients with disease limited to the joints have a lower frequency, at levels equivalent to those seen among healthy age-matched persons.…”

Section: Discussionsupporting

confidence: 91%

“…In contrast, there is an even higher level of in vivo accumulation of CD56ϩ T cells among RA patients, which is disproportionate with age. Similar age-related in vivo accumulation of CD28-null T cells has been reported (23,24), whereas RA patients have even higher frequencies irrespective of age (8,9) (Figure 2A). These findings support the idea of accelerated senescence in 54 MICHEL ET AL RA (17), with CD28-null,CD56ϩ T cells being prototypic senescent or presenescent lymphocytes.…”

Section: Discussionsupporting

confidence: 83%

“…CD4 and CD8 compartments, and the frequency of CD28-null T cells correlates with disease activity of RA (8)(9)(10). CD4ϩ,CD28-null T cells are associated with severe extraarticular disease manifestations (8) that are known to be risk factors for excess/accelerated mortality in RA (11).…”

mentioning

confidence: 99%

“…We examined lymphocytes from patients with RA, who are expected to display T cell phenotypes that reflect persistent immune activation in vivo (9,18). We also examined an in vitro chronic activation system to monitor the development of senescent CD28-null T cells from polyclonal CD28ϩ precursors (12).…”

mentioning

confidence: 99%

“…We also examined an in vitro chronic activation system to monitor the development of senescent CD28-null T cells from polyclonal CD28ϩ precursors (12). Since CD28 is subject to modulation either in response to activating stimuli in vitro (19,20) or as a consequence of persistent immune activation in vivo (9,10), this experimental strategy is a reasonable approach to identifying receptors on chronically activated T cells. Here we document the expansion of CD28-null T cells that express CD56, the prototypical receptor of natural killer (NK) cells (21).…”

mentioning

confidence: 99%

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CD56‐expressing T cells that have features of senescence are expanded in rheumatoid arthritis

Michel

Turesson

Lemster

et al. 2007

Arthritis & Rheumatism

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Objective. T cells deficient in CD28 expression have been implicated in the pathogenesis of rheumatoid arthritis (RA). Given that CD28-null T cells are functionally heterogeneous, we undertook this study to screen for novel receptors on these cells.Methods. Seventy-two patients with RA (ages 35-84 years) and 53 healthy persons (32 young controls ages 19-34 years, 21 older controls ages 39-86 years) were recruited. Phenotypes and proliferative capacity of T cells from fresh leukocytes and of long-term cultures were monitored by flow cytometry. Lung biopsy specimens from patients with RA-associated interstitial pneumonitis (IP) were examined by immunohistochemistry. Receptor functionality was assessed by crosslinking bioassays.Results. Chronic stimulation of CD28؉ T cells in vitro yielded progenies that lacked CD28 but that gained CD56. Ex vivo analysis of leukocytes from patients with extraarticular RA showed a higher frequency of CD56؉,CD28-null T cells than in patients with disease confined to the joints or in healthy controls. CD56؉,CD28-null T cells had nil capacity for proliferation, consistent with cellular senescence. CD56؉ T cells had skewed T cell receptor (TCR) ␣/␤-chain usage and restricted TCR third complementarity-determining region spectra. Histologic studies showed that CD56؉ T cells were components of cellular infiltrates in RAassociated IP. CD56 crosslinking on T cells sufficiently induced cytokine production, although CD56/TCR coligation induced higher production levels.Conclusion. Chronic activation of T cells induces counterregulation of CD28 and CD56 expression. The loss of CD28 is accompanied by the gain of CD56 that confers TCR-independent and TCR-dependent activation pathways. We propose that accumulation of CD56؉ T cells in RA contributes to maladaptive immune responses and that CD56؉ T cells are potential targets for therapy.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 83%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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CD56‐expressing T cells that have features of senescence are expanded in rheumatoid arthritis

Michel

Turesson

Lemster

et al. 2007

Arthritis & Rheumatism

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Modulation of CD28 expression with anti–tumor necrosis factor α therapy in rheumatoid arthritis

Bryl¹,

Vallejo²,

Matteson³

et al. 2005

Arthritis & Rheumatism

125

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Objective. The immune system of patients with rheumatoid arthritis (RA) is characterized by the accumulation of CD4؉ T cells deficient in CD28 expression and the up-regulation of tumor necrosis factor ␣ (TNF␣). Previous in vitro studies have shown that TNF␣ induces transcriptional silencing of the CD28 gene. Because reduced expression of CD28 in T cells compromises immunocompetence, we examined whether CD28 expression is reduced in patients with RA in vivo and whether the reduction is related to TNF␣.Methods. Patients with RA and age-matched individuals were recruited. Peripheral blood mononuclear cells were stained for CD3, CD4, CD8, CD28, TNF receptor I (TNFRI), and TNFRII, and analyzed by quantitative flow cytometry. The number of CD28 and TNFR molecules was monitored in a subgroup of patients with RA undergoing treatment with anti-TNF␣.Results. In addition to higher frequencies of CD28 null T cells, patients with RA had significantly reduced numbers of CD28 and TNFRI molecules on CD4؉,CD28؉ T cells. Normal expression could be restored in vitro by overnight culture, suggesting that CD28 in patients was modulated by exogenous factors. In contrast, treatment with TNF␣ in vitro resulted in further down-regulation. CD28 expression was normalized in patients undergoing TNF␣-neutralizing therapy.Conclusion. Overproduction of TNF␣ in RA induces a global down-regulation of CD28 in CD4؉ T cells and may cause reduced sensitivity to costimulatory signals in T cell responses.

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Effect of tumor necrosis factor α inhibition on CD28 surface expression on CD4+ T cells

Gerli¹,

Bocci²,

Shoenfeld³

2006

Arthritis & Rheumatism

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Cell Surface CD28 Levels Define Four CD4+ T Cell Subsets: Abnormal Expression in Rheumatoid Arthritis

Cited by 31 publications

References 57 publications

CD56‐expressing T cells that have features of senescence are expanded in rheumatoid arthritis

CD56‐expressing T cells that have features of senescence are expanded in rheumatoid arthritis

Modulation of CD28 expression with anti–tumor necrosis factor α therapy in rheumatoid arthritis

Effect of tumor necrosis factor α inhibition on CD28 surface expression on CD4+ T cells

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