A CIITA‐independent pathway that promotes expression of endogenous rather than exogenous peptides in immune‐privileged sites

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Abstract
A CIITA‐independent pathway of MHC class II expression has been found in the eye and the brain, both immune‐privileged sites. Although corneal endothelial cells were unable to express MHC class II in response to IFN‐γ alone, these cells readily expressed MHC class II molecules via a CIITA‐independent pathway when triggered by simultaneous exposure to IFN‐γ and TNF‐α. CIITA‐independent expression of MHCclass II molecules enabled corneal endothelial cells to present cytosolic, but not endosomal, ovalbumin (OVA) to OVA‐primed T cells. To determine whether CIITA‐independentexpression of MHC class II is relevant in vivo, minor H‐only‐incompatible corneal allografts prepared from CIITA knockout (KO) mice, MHC class II KO mice or wild‐type donors were placed ineyes of normal mice. Cornea allografts from wild‐type and CIITA KO mice suffered similar rejection fates, whereas far fewer class II‐deficient corneas were rejected. In addition, MHC class II‐bearing macrophages were observed in cuprizone‐induced inflammatory and demyelinating brain lesions of CIITA KO mice. We conclude that class II expression via the CIITA‐independent pathway enhances the vulnerability to rejection of corneal grafts expressing minor antigens. The potential relevance of CIITA‐independent MHC class II expression at immune‐privileged sites is discussed in relation to tolerance to strong autoantigens.