Defective B7 expression on antigen-presenting cells underlying T cell activation abnormalities in systemic lupus erythematosus (SLE) patients

Abstract

SUMMARYDefective T cell functions, including IL-2 production and proliferation, have been shown in SLE patients. After T cell stimulation (first signal), a costimulatory signal (second signal) is required to achieve complete T cell activation. Main costimulatory signals are provided to T cells by B7 antigens (CD80 and CD86, expressed on antigen-presenting cells (APC)) upon interaction with its receptor, the CD28 molecule expressed on T cells. The aim of this study was to investigate the role of CD28/B7 interactions in the impaired T cell responses of SLE patients. We show that stimulation of T cells with phytohaemagglutinin (PHA) in the presence, but not in the absence, of anti-CD28 MoAb or B7 cells results in tyrosine phosphorylation of specific substrates, transcription of mRNA and production of IL-2 that is indistinguishable in SLE patients and healthy controls. Moreover, proliferation of costimulated T cells from SLE and controls was specifically abrogated by blocking the CD28/B7 interactions by means of addition to the culture of the CTLA4-Ig fusion protein. However, in most patients activated APC failed to up-regulate B7 molecules, giving rise to ineffective costimulatory signalling to T cells. These results indicate that the CD28/B7 costimulatory pathway is defective in SLE patients.

IL-6 Produced by Dendritic Cells from Lupus-Prone Mice Inhibits CD4+CD25+ T Cell Regulatory Functions

“…The reduction in expression level of activation markers on TC DCs is overall similar to what has been described in lupus patients (25)(26)(27) and more recently in NZM2410, B6.TC parental strain (28). Some differences in relative CD40 and CD86 expression between B6.TC and NZM2410 may be due to the non-Sle loci.…”

“…The number of circulating plasmacytoid DCs (pDCs) is reduced in lupus patients (19,20), and the number of total DCs is increased in the lymphoid organs of lupus-prone mice (21)(22)(23)(24). Abnormal costimulatory profiles have also been reported in lupus patients (25)(26)(27) and in BWF 1 or NZM2410 mice (28). DC functions have also been implicated in the pathogenesis of lupus.…”

T cells in the pathogenesis of systemic lupus erythematosus: Potential roles of CD154-CD40 interactions and costimulatory molecules

“…Freshly isolated monocytes from SLE patients and controls express similar levels of these costimulatory molecules (CD86 >> CD80) [58]. However, following co-culture of peripheral blood mononuclear cells with mitogenic lectins or stimulation with IFN-␥, there is diminished upregulation of CD80 and CD86 expression on SLE monoctyes relative to cells from normal individuals [58,59]. It has been known for several years that some SLE patients demonstrate defective T cell IL-2 production and proliferation following stimulation with recall Ags.…”

“…The demonstration of abnormal IFN-␥ induced upregulation of CD80 and CD86 expression on SLE monocytes provides a molecular basis that at least partially accounts for this defect. In this regard, directly signaling CD28, therefore bypassing the requirement for CD80 and CD86 upregulation, restores to normal the tyrosine phosphorylation pattern and IL-2 production of SLE T cells stimulated with submitogenic lectin concentrations [59] or IL-2 production and proliferative responses of SLE T cells stimulated with tetanus toxoid [61].…”

Antisense Cyclic Adenosine 5′-Monophosphate Response Element Modulator Up-Regulates IL-2 in T Cells from Patients with Systemic Lupus Erythematosus

“…Systemic lupus erythematosus (SLE) patients often suffer and die from overwhelming infections, and decreased IL-2 production in response to antigenic stimuli represents one of the many contributing factors (8,9). Inability of SLE T cells to produce IL-2 is important because on the one hand it diminishes the T cell response to Ags and on the other hand it fails to promote the activation-induced cell death of T cells, which is necessary to terminate the immune response (1).…”