Soluble Peptide Treatment Reverses CD8 T Cell-Induced Disease in a Mouse Model of Spontaneous Tissue-Selective Autoimmunity
Autoimmunity is a complex process that involves recognition of self antigens by autoreactive T cells or tissue targeting by autoantibodies produced by B cells. Specific molecular targets have been identified in several autoimmune diseases but remain unknown in many others. Transgenic (Tg) mice have been utilized to express model antigens that can be recognized by T cells or by autoantibodies. To identify mechanisms by which CD8+ autoreactive T cells cause inflammation, we generated a double transgenic (DTg) murine model of autoimmunity by crossing K14-sOVA mice, which express soluble chicken ovalbumin (OVA), with OT-1 mice, whose CD8 T cells express V2/V5 regions of the T cell receptor that are specific for SIINFEKL peptide (OVA 257-264) in association with class I MHC molecules. The K14-SOVA/OT-1 (#5 and #17) DTg mice develop normally, except that they undergo a destructive process that selectively targets the external pinnae in the first 6 days of life. The purpose of this study was to elucidate the mechanism and attempt to obviate the resulting tissue-specific destruction. By light microscopy, the ear bud area displayed an intense inflammatory infiltrate of V2/V5+CD8+ OT-1 cells when characterized by FACS. Administration of the TCR-recognized SIINFEKL peptide i.v. to pregnant F1 mice on days E16 and E18 in utero and i.p. to newborn pups on days 2 and 4 prevented the inflammatory response and resulted in development of normal-looking ears in 100% of pups. Treatment with the SIINFEKL peptide was shown to down-regulate the CD8 coreceptor and activate T-cells to differentiate into memory T-cells. This model can inform us about mechanisms of peripheral tolerance and potential therapies for autoimmune diseases in which specific molecular targets are known.
Peptide Fragments, T-Lymphocytes, Autoimmunity
University of Texas Southwestern Medical Center
Networked Digital Library of Theses and Dissertations