Central Role of Thrombospondin-1 in the Activation and Clonal Expansion of Inflammatory T Cells

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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.

Section: Methodsmentioning

confidence: 99%

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

Michel

Turesson

Lemster

et al. 2007

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“…FLS-derived signals have previously been demonstrated to support the growth of autoreactive T cells (40,41). Through their responsiveness to lymphocytederived cytokines such as LT␤, resident FLS become active participants in the process of ectopic lymphoorganogenesis.…”

Section: Discussionmentioning

confidence: 99%

Lymphotoxin β–mediated stimulation of synoviocytes in rheumatoid arthritis

Braun¹,

Takemura²,

Vallejo³

et al. 2004

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Objective. Lymphotoxin ␤ (LT␤), a cytokine produced by T cells and B cells, plays a central role in the normal development of lymph nodes and is critical in the formation of ectopic germinal center reactions in rheumatoid synovitis. Because resident fibroblast-like synoviocytes (FLS) express receptors for LT␤, we examined the consequences of FLS activation by LT␤.Methods. FLS from patients with rheumatoid arthritis were isolated and examined for the expression of LT␤ receptor. FLS were incubated with LT␣1␤2 and assayed for the production of cytokines and chemokines and the up-regulation of adhesion molecules.Results. Exposure of FLS to recombinant LT␣1␤2 resulted in the production of multiple inflammatory cytokines and metalloproteinases, implicating FLS as amplifiers of the inflammatory process in the inflamed joint. Additionally, LT␣1␤2 was found to up-regulate the expression of cell adhesion molecules, rendering FLS to efficient adhesion substrates for T cells. LT␣1␤2 also induced production of the chemokines CCL2 and CCL5, which elicited transmigration activity of T cells. Upon stimulation with LT␣1␤2, FLS did not acquire characteristics of follicular dendritic cells.Conclusion. These data document that FLS are involved in multiple stages of the inflammatory process, including the recruitment and retention of lymphocytes in the synovial microenvironment. We propose that the heterotypic interaction between LT␤-producing lymphocytes and responding FLS contributes to the establishment of complex lymphoid microstructures, and that this may be one element that defines susceptibility of the synovial membrane to lymphoid organogenesis.

“…They also have large cytoplasmic stores of interferon-␥ (20), express the chemokine receptor CCR5 (21), and up-regulate CD161 (22), a molecule that facilitates tissue invasion. Hence, CD4ϩ,CD28 null T cells are equipped to infiltrate sites of inflammation, where they amplify local inflammatory and autoimmune cascades (22,23).…”

Section: Conclusion Overproduction Of Tnf␣ In Ra Induces a Global Domentioning

confidence: 99%

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

Bryl¹,

Vallejo²,

Matteson³

et al. 2005

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125

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.