Unchecked CD70 Expression on T Cells Lowers Threshold for T Cell Activation in Rheumatoid Arthritis

Lee, Won Woo; Yang, Zhi Zhang; Li, Guangjin; Weyand, Cornelia M.; Goronzy, Jörg J.

doi:10.4049/jimmunol.179.4.2609

Cited by 83 publications

(59 citation statements)

References 49 publications

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“…Several diseases characterized by chronic infection or chronic inflammation, such as HIV-1 or chronic LCMV infection (16,17), systemic lupus erythematosus (18), or rheumatoid arthritis (19), are accompanied by constitutive up-regulation of CD70 expression. CD70 is a molecule of the TNF superfamily that promotes proliferation and acquisition of effector function of T cells after binding CD27.…”

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confidence: 99%

Chronic CD70-Driven Costimulation Impairs IgG Responses by Instructing T Cells to Inhibit Germinal Center B Cell Formation through FasL-Fas Interactions

Beishuizen

Kragten

Boon³

et al. 2009

The Journal of Immunology

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CD70 provides costimulation that enhances effector T cell differentiation upon binding of its receptor, CD27. During chronic immune activation, CD70 is constitutively expressed on activated immune cells, and this induces T cell-driven disruption of neutralizing Ab responses via an unknown mechanism. We used CD70-transgenic mice to investigate the effect of constitutive expression of CD70 on T cell-dependent B cell responses. CD70 induced up-regulation of the B cell follicle homing chemokine receptor CXCR5 on T cells, enabling not only CD4 but also CD8 T cells to infiltrate the B cell follicles. CD70-transgenic mice failed to develop productive germinal center formation and displayed impaired IgG Ab responses. Defective germinal center B cell differentiation was critically dependent on CD70-mediated CD27 signaling in T cells, and involved Fas-dependent impairment of germinal center B cell differentiation. Thus, CD70-driven costimulation enables T cells to terminate B cell responses, thereby compromising durable Ab production. Our findings imply that the CD70- and CD27-driven costimulatory axis may be involved in shutdown of B cell responses before clearance of Ag. Because CD70 is expressed constitutively in chronic viral infections such as HIV-1 infection, this mechanism may also contribute to defects in humoral immunity associated with this disease.

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confidence: 99%

Chronic CD70-Driven Costimulation Impairs IgG Responses by Instructing T Cells to Inhibit Germinal Center B Cell Formation through FasL-Fas Interactions

Beishuizen

Kragten

Boon³

et al. 2009

The Journal of Immunology

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“…A similar increased gene expression with age and in particular in effector cells has also been reported for other demethylation-sensitive genes such as CD11a and CD70. [38][39][40] If KIR promoter demethylation in T cells is the local sequel of a global defect, how can it be CD8 T cell-subset specific? CD4 and CD8 T cells have several similarities in regulating KIR transcription.…”

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confidence: 99%

Epigenetic regulation of killer immunoglobulin–like receptor expression in T cells

Weyand

et al. 2009

Blood

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IntroductionWith increasing age, the ability of the immune system to protect against new antigenic challenges or to control chronic infection erodes. 1 Elderly persons are more likely to develop bacterial infections in lungs, skin, and the urinary tract. 2 The incidence and severity of viral infections increases, and the responses to prophylactic vaccinations decline. [3][4][5][6][7] A dwindling in thymic production of naive T cells, resulting in a decreasing size and diversity of the naive cell compartment, contributes to the defective adaptive immune response. [8][9][10] However, the immune defect is not limited to naive T cells; memory T cells and, in particular, CD8 T cells are also affected by aging. Central memory CD8 T cells decline at the expense of end-differentiated CD8 effector T cells. 11 In parallel, CD8 T cells undergo phenotypic changes that are of functional importance. 12 CD8 T cells tend to lose the expression of the CD28 molecule and are, therefore, less responsive to stimulation by antigen-presenting cells. Because cross-presentation of antigen by dendritic cells is an important pathway to elicit CD8 responses to viral infections, the CD28 loss has a negative effect. 13,14 More important than the CD28 loss may be the de novo expression of negative regulatory receptors that occurs on many CD8 T cells. 15,16 The best-studied receptors so far are the killer immunoglobulinlike receptors (KIRs) that recognize MHC class I variants. KIRs are a multigene family encoded within the leukocyte receptor cluster on chromosome 19 and comprise inhibitory and, less frequently, stimulatory receptors. 17,18 Inhibitory receptors have ITIM motifs in their cytoplasmic domains and recruit SHP-1 that dephosphorylates various tyrosine kinases in the early T-cell receptor (TCR) signaling pathway. 19,20 On antigenic stimulation of the TCR, the KIR receptor recognizes an MHC class I ligand on the very same target cell, is recruited to the TCR recognition complex, and enters the central supramolecular activation cluster with a delay of approximately 30 minutes. 21 This delay is sufficient to not compromise effector cell functions such as cytotoxicity; however, the eventual recruitment of KIRs to the antigen-recognition complex prematurely terminates TCR signaling and inhibits activation-induced transcription that requires sustained stimulation such as the initiation of T-cell proliferation and cytokine transcription.The mechanisms that drive increasing KIR expression on T cells with age are unclear. KIRs are primarily expressed on natural killer (NK) cells where they are clonally distributed. 22 The clonal distribution pattern is entirely maintained by CpG DNA methylation. Inhibition of the DNA methyltransferase (DNMT) by 5-aza-2Ј-deoxycytidine (5-Aza-dC) leads to a global expression of KIRs on all NK cells. 23,24 Previous studies have shown that transcriptional control of KIR expression differs in T cells compared with NK cells; however, even naive CD4 T cells have the transcriptional machinery to support the activation...

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“…In addition to the normal role of CD70 in mounting an immune response, a role for CD70 in autoimmunity and chronic inflammatory conditions has also been proposed by several reports (35)(36)(37)(38). For example, CD4 T cells in the synovium of rheumatoid arthritis (RA) and psoriatic arthritis patients have been shown to express high levels of CD70.…”

mentioning

confidence: 99%

“…The fact that T cells from SLE patients elicit enhanced Ig secretion by B cells, which can be abrogated with a blocking anti-CD70 Ab, further implicates a role for CD70 in the pathogenesis of this disease (35). CD70 overexpression on T cells in SLE patients is shown to be due to hypomethylation of DNA sequences that flank the CD70 promoter, which results in an inability to down-regulate CD70 expression once it is induced by the activation of T cells (36,37,39). Similarly, an increase in splenic CD70 expressing CD4 T cells has also been documented in the lupus-prone MRL/lpr strain of mice, which is also caused by defective DNA methylation of the CD70 gene (40).…”

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confidence: 99%

Blocking of CD27-CD70 Pathway by Anti-CD70 Antibody Ameliorates Joint Disease in Murine Collagen-Induced Arthritis

Oflazoglu

Boursalian

Zeng

et al. 2009

The Journal of Immunology

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Rheumatoid arthritis (RA) is characterized by inflammation and cellular proliferation in the synovial lining of joints that result in cartilage and bone destruction. Although the etiology of RA is unclear, activated lymphocytes and proinflammatory molecules, in particular TNF superfamily members, have been implicated in the disease pathology. A TNF superfamily member, CD70, is found on activated lymphocytes and shown to be important in memory and effector responses of lymphocytes. CD70 is expressed at high levels on chronically activated T cells in patients with autoimmune disorders, including RA. The involvement of CD70 in the progression of RA, however, remains unknown. In this study, we report effects of targeting CD70 on disease pathogenesis by using an anti-mouse CD70 Ab in a murine model of collagen-induced arthritis (CIA). In addition to blocking CD70 binding to its receptor CD27, the anti-CD70 Ab used also engages Fc-dependent effector functions including Ab-dependent cellular cytotoxicity, phagocytosis, and complement fixation. Treatment of mice with anti-CD70 Ab both before the onset or after the established disease in CIA model resulted in marked improvements in disease severity and significant reduction in the production of autoantibodies. Histopathological analyses of the joints of mice revealed a substantial reduction of inflammation, and bone and cartilage destruction in response to the anti-CD70 Ab treatment. These results uncover a novel role for CD27-CD70 interactions in the regulation of in vivo inflammatory response leading to arthritis, and provide a molecular basis to support the rationale for anti-CD70 therapy for autoimmune and inflammatory diseases.

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Unchecked CD70 Expression on T Cells Lowers Threshold for T Cell Activation in Rheumatoid Arthritis

Cited by 83 publications

References 49 publications

Chronic CD70-Driven Costimulation Impairs IgG Responses by Instructing T Cells to Inhibit Germinal Center B Cell Formation through FasL-Fas Interactions

Chronic CD70-Driven Costimulation Impairs IgG Responses by Instructing T Cells to Inhibit Germinal Center B Cell Formation through FasL-Fas Interactions

Epigenetic regulation of killer immunoglobulin–like receptor expression in T cells

Blocking of CD27-CD70 Pathway by Anti-CD70 Antibody Ameliorates Joint Disease in Murine Collagen-Induced Arthritis

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