Cd4+ T Cells from Lupus-Prone Mice Are Hyperresponsive to T Cell Receptor Engagement with Low and High Affinity Peptide Antigens

Autoantibodies directed against dsDNA are found in patients with systemic lupus erythematosus as well as in mice functionally deficient in either Fas or Fas ligand (FasL) (lpr/lpr or gld/gld mice). Previously, an IgH chain transgene has been used to track anti-dsDNA B cells in both nonautoimmune BALB/c mice, in which autoreactive B cells are held in check, and MRL-lpr/lpr mice, in which autoantibodies are produced. In this study, we have isolated the Fas/FasL mutations away from the autoimmune-prone MRL background, and we show that anti-dsDNA B cells in Fas/FasL-deficient BALB/c mice are no longer follicularly excluded, and they produce autoantibodies. Strikingly, this is accompanied by alterations in the frequency and localization of dendritic cells as well as a global increase in CD4 T cell activation. Notably, as opposed to MRL-lpr/lpr mice, BALB-lpr/lpr mice show no appreciable kidney pathology. Thus, while some aspects of autoimmune pathology (e.g., nephritis) rely on the interaction of the MRL background with the lpr mutation, mutations in Fas/FasL alone are sufficient to alter the fate of anti-dsDNA B cells, dendritic cells, and T cells.

Section: Discussionsupporting

confidence: 64%

Fas/Fas Ligand Deficiency Results in Altered Localization of Anti-Double-Stranded DNA B Cells and Dendritic Cells

Fields

Sokol

Eaton-Bassiri

et al. 2001

“…Our findings provide support to the position that cell excitability may predispose to autoimmunity. Vratsanos et al (21) reported that T cells from MRL TCR transgenic mice responded better to cognate Ag than cells from control animals. Heightened responses have also been encountered among B cells from patients with SLE (28) and graft vs host mice that develop autoimmunity (20).…”

Section: Discussionmentioning

confidence: 99%

“…Notable is that this altered composition of CD3 in SLE T cells is associated with a higher magnitude signaling process, that is, with increased free intracytoplasmic calcium [Ca 2ϩ ] i response and protein tyrosine phosphorylation responses (17)(18)(19). Increased Ag receptorinitiated signaling in a graft vs host model heralds the ignition of autoimmunity (20), and cognate Ag stimulation in the TCR transgenic MRL mouse leads to T cell hyperresponsiveness and autoimmune manifestations (21). Therefore, it seems that in both humans and mice increased lymphocyte excitability is associated with autoimmunity.…”

Section: Forced Expression Of the Fc Receptor ␥-Chain Renders Human Tmentioning

confidence: 99%

Forced Expression of the Fc Receptor γ-Chain Renders Human T Cells Hyperresponsive to TCR/CD3 Stimulation

Nambiar

Fisher

Kumar

et al. 2003

High level expression of FcεRIγ chain replaces the deficient TCR ζ-chain and contributes to altered TCR/CD3-mediated signaling abnormalities in T cells of patients with systemic lupus erythematosus. Increased responsiveness to Ag has been considered to lead to autoimmunity. To test this concept, we studied early signaling events and IL-2 production in fresh cells transfected with a eukaryotic expression vector encoding the FcεRIγ gene. We found that the overexpressed FcεRIγ chain colocalizes with the CD3ε chain on the surface membrane of T cells and that cross-linking of the new TCR/CD3 complex leads to a dramatic increase of intracytoplasmic calcium concentration, protein tyrosine phosphorylation, and IL-2 production. We observed that overexpression of FcεRIγ is associated with increased phosphorylation of Syk kinase, while the endogenous TCR ζ-chain is down-regulated. We propose that altered composition of the CD3 complex leads to increased T cell responsiveness to TCR/CD3 stimulation and sets the biochemical grounds for the development of autoimmunity.

“…Studies also support an important role for regulatory T cells in protection from autoimmunity in the periphery (4,5). Alternatively, the activation of low-affinity autoreactive T cells in the normal repertoire may require a higher threshold of self-peptide-MHC interaction (6,7). Finally, some self-Ags lacking expression in the thymus may not participate in negative selection and depletion of the self-reactive repertoire.…”

Section: B Cells Drive Early T Cell Autoimmunity In Vivo Prior Tomentioning

confidence: 99%

B Cells Drive Early T Cell Autoimmunity In Vivo prior to Dendritic Cell-Mediated Autoantigen Presentation

Yan

Harvey

Gee

et al. 2006

107

Both B cells and dendritic cells (DCs) have been implicated as autoantigen-presenting cells in the activation of self-reactive T cells. However, most self-proteins are ubiquitously and/or developmentally expressed, making it difficult to determine the source and the exposure of autoantigens to APCs in a controlled manner. In this study, we have used an Ig transgenic mouse model to examine the mechanisms by which B cells and other APCs acquire and present lupus autoantigens in vivo. Targeting a lupus autoantigen, the small nuclear ribonucleoprotein particle D protein, to the BCR activates autoreactive T cells in the periphery. Our in vivo studies demonstrate that autoantigen-specific B cells, when present in the repertoire, are the first subset of APCs to capture and present self-proteins for activating T cells. Thereafter, DCs acquire self-Ag and become effective APCs for stimulating the same subsets of autoreactive T cells. This mechanism provides one explanation of how early steps in autoimmunity can focus responses, via BCR, at a small group of self-proteins among the total milieu of intracellular self-proteins. Subsequently, DCs and other professional APCs may then amplify and perpetuate the autoimmune T cell response.