Abstract
Abrogating an unwanted immune response toward a specific antigen without compromising the entire immune system is a hoped-for goal in immunotherapy. Instead of manipulating dendritic cells and suppressive regulatory T cells, depleting effector T cells or blocking their co-stimulatory pathways, we describe a method to specifically inhibit the presentation of an antigen eliciting an unwanted immune reaction. Inclusion of an oxidoreductase motif within the flanking residues of MHC class II epitopes polarizes CD4+ T cells to cytolytic cells capable of inducing apoptosis in antigen presenting cells (APCs) displaying cognate peptides through MHC class II molecules. This novel function results from an increased synapse formation between both cells. Moreover, these cells eliminate by apoptosis bystander CD4+ T cells activated at the surface of the APC. We hypothesize that they would thereby block the recruitment of cells of alternative specificity for the same autoantigen or cells specific for another antigen associated with the pathology, providing a system by which response against multiple antigens linked with the same disease can be suppressed. These findings open the way toward a novel form of antigen-specific immunosuppression.
Highlights
A Distinct Subset of CD4+ T CellsCD4+ T cells with cytotoxic activity have been occasionally described over the past 30 years [1,2,3]
Natural Tregs are essential for the control of autoimmunity and have shown a therapeutic potential in experimental autoimmune diseases and Eliciting cytolytic CD4+ T cells allograft rejection [17], but their use is still limited by difficulties of expanding stable populations, their lack of antigen specificity and concern of non-specific effect related to the production of suppressive cytokines [18]
Formation of a synapse in between an antigen presenting cell (APC) expressing a MHC class II molecule presenting an antigenderived epitope and a CD4+ T cell constitutes the earliest step of recognition by the adaptive immune system, and as such represents an ideal target for intervention
Summary
CD4+ T cells with cytotoxic activity have been occasionally described over the past 30 years [1,2,3]. The determinants in this peptide sequence that lead to this remarkable property were unknown Extensive investigation of this epitope unveiled the presence of an intact amino terminal oxidoreductase motif (CxxS motif, where C stands for cysteine, S for serine, and x for any other amino acid) located within the flanking residues. Amino acid substitution assays demonstrated that the presence of this motif in the Der p 2 (p21–35) sequence is essential for acquisition of cytolytic activities toward APCs [32] Introducing such motif in the flanking residues of other T cell epitopes demonstrates that the cytolytic properties are not limited to the specific Der p 2 epitope sequence context. The natural CxxS motif was further optimized by introducing a second cysteine, making a CxxC motif [33] presenting a higher oxidoreductase and reinforcing the cytolytic properties This novel function results from an increased synapse formation between the APC and the antigen-specific CD4+ T cells. Carlier et al further demonstrated that the target for the reduction was a constrained disulfide bridge located in the second extracellular domain of the CD4 molecule itself
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