The three dimensions of functional T-cell tolerance: from research to practice

Transgenic (Tg) mouse models of autoimmunity have been utilized to express model antigens that can be recognized by T cells or by autoantibodies. To identify mechanisms of CD8-mediated tissue-specific autoimmune reactions and to identify potential treatments, we generated a double transgenic (DTg) murine model of autoimmunity by crossing K14-sOVA mice, which express soluble chicken ovalbumin (OVA) predominantly in external ear skin, with OT-I mice whose CD8 T cells express Vα2/Vβ5 regions of the T cell receptor and are specific for SIINFEKL peptide (OVA 257-264) in association with class I MHC. The K14-sOVA/OT-I DTg mice develop a destructive process selectively targeting the external ear pinnae in the first 6 days of life. The ear bud area develops an intense inflammatory infiltrate of OT-I cells. Administration of the SIINFEKL peptide i.v. to pregnant F1 mice and subsequently i.p. to newborn pups resulted in normal external ear development. Treatment with this self-peptide markedly reduced OT-I cell numbers as well as down-regulated the CD8 co-receptor. This model can be useful in studying localized, tissue-specific, immune-mediated skin disease and inform us about potential therapies for autoimmune diseases in which specific molecular targets are known.