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A peptide-based tolerizing vaccine against autoimmune arthritis directly interacting with antigen-specific T cells

ABSTRACT: A longstanding goal has been to find an antigen-specific preventive therapy, i.e., a vaccine, for autoimmune diseases. Major hindrances have so far been to select natural regulatory antigen targets and side-effects induced by clustering the T cell receptor (TCR) or activating the costimulatory signals. Here we show that the administration of a mouse major histocompatibility complex class II protein binding a unique galactosylated collagen type II (COL2) peptide (Aq-galCOL2) directly interacts with the antigen specific TCR, and expands peripheral regulatory T cells, displaying a potent dominant suppressive effect and protection of collagen induced arthritis. The therapeutic effect is dominant and tissue specific as it is possible to transfer the effect with induced regulatory T cells and downregulate autoimmune arthritis induced by other antigens than COL2 or by passive transfer of antibodies. Thus, the here described tolerogenic approach may be a promising dominant antigen-specific therapy for RA, and in principle, for autoimmune diseases in general.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Primary Cell, T Cell

SUBMITTER: Christian Beusch

LAB HEAD: Rikard Holmdahl

PROVIDER: PXD034792 | Pride | 2023-06-15

REPOSITORIES: Pride

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Project description:Background. T cells in the thymus undergo opposing positive and negative selection processes so that the only T cells entering circulation are those bearing a T cell receptor (TCR) with a low affinity for self. The mechanism differentiating negative from positive selection is poorly understood, despite the fact that inherited defects in negative selection underlie organ-specific autoimmune disease in AIRE-deficient people and the non obese diabetic (NOD) mouse strain. Results. Here we use homogeneous populations of T cells undergoing either positive or negative selection in vivo together with genome-wide transcription profiling on microarrays to identify the gene expression differences underlying negative selection to an Aire-dependent organ-specific antigen, including the upregulation of a genomic cluster in the cytogenetic band 2F. Analysis of defective negative selection in the autoimmune-prone NOD strain demonstrates a global impairment in the induction of the negative selection response gene set, but little difference in positive selection response genes. Combining expression differences with genetic linkage data we identify differentially expressed candidate genes including Bim, Bnip3, Smox, Pdrg1, Id1, Pdcd1, Ly6c, Pdia3, Trim30 and Trim12. Conclusions. The data provide a molecular map of the negative selection response in vivo, and by analysis of deviations from this pathway in the autoimmune susceptible NOD strain, suggest that susceptibility arises from small expression differences in genes acting at multiple points in the pathway between the TCR and cell death. Experiment Overall Design: Analysis of two thymic populations - early single positive thymocytes (CD4+CD8lowCD69+TCRhi) and early double positive thymocytes (CD4+CD8+CD69-TCRlow). Samples purified from the 3A9 TCR transgenic (TCR) to characterise positive selection and the 3A9 TCR x insHEL double transgenic (Dbl) to characterise negative selection towards an Aire-dependent organ-specific antigen. Both the non autoimmune C57BL10.H2k (B10) and autoimmune Non obese diabetic (NOD) strains were analysed in this method. Three biological replicates were used for each of these eight different groups.

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	210326_VU_fraction4.raw	Raw
	210326_VU_fraction5.raw	Raw

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A peptide-based tolerizing vaccine against autoimmune arthritis directly interacting with antigen-specific T cells

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