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

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-+ alone, these cells readily expressed MHC class II molecules via a CIITA-independent pathway when triggered by simultaneous exposure to IFN-+ and TNF- § . 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-independent expression 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 in eyes 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.

T‐cell “induced‐self” MHC class I/peptide complexes may enable “de novo” tolerance induction to neo‐antigens occurring outside of the thymus

“…Consequences of the induced epithelial self‐epitopes may heavily depend upon the thymic output of naïve neo‐antigen‐reactive cells and may alter the activation status of the T‐cell repertoire via re‐stimulation and possible clonal expansion ((Figure A,B) ,s13–s18). It is now recognized that specialized compartments induce a tissue‐specific regulatory phenotype . As exactly these antigen‐specific silenced T cells may gain access to their thymic origin once again, peripherally induced T‐cell maturation may well then alter the antigen‐specific thymic selection or differentiation process, even of CD4+ regulatory T cells (Figure B).…”

“…It is now recognized that specialized compartments induce a tissue-specific regulatory phenotype. [8,9] As exactly these antigen-specific silenced T cells may gain access to their thymic origin once again, peripherally induced T-cell maturation may well then alter the antigen-specific thymic selection or differentiation process, even of CD4+ regulatory T cells ( Figure 1B). Phrased provocatively, autoimmunity to peripheral tissue antigens, such as in AA, represents an undesired, adverse effect of developing and then encountering novel self-antigens.…”

“…proliferating from differentiating, malignant or stressed cells. [6,8,9] Neo-antigenic structures may also be generated by tissue remodelling, genetic or metabolic alterations or even abnormalities in protein (antigen) degradation.…”

TNF-α Induces Macroautophagy and Regulates MHC Class II Expression in Human Skeletal Muscle Cells

“…The MHC class II transactivator, a transcriptional coactivator, is the key intermediate that directs constitutive and IFN-␥-inducible expression of MHC class II genes in professional and nonprofessional antigenpresenting cells, respectively (43). It has previously been suggested that TNF-␣ augments MHC class II expression through a mechanism downstream or independent of class II transactivator induction in nonprofessional antigen-presenting cells (44) and that class II transactivator-independent MHC class II induction mediated by TNF-␣ promotes expression of endogenous rather than exogenous peptides in immune-privileged sites (45). Our data on TNF-␣-mediated macroautophagy induction and MHC class II regulation suggest that TNF-␣ regulates MHC class II expression levels via delivery of autophagosome content to the MHC class II compartments for efficient MHC class II loading and successive release to the cell surface.…”

Loss of major histocompatibility class II expression in non-immune-privileged site diffuse large B-cell lymphoma is highly coordinated and not due to chromosomal deletions

“…Lack of invariant chain expression, which frequently occurs in immune-privileged sites, favors the presentation of endogenous as opposed to exogenous peptides that may alter details of the inflammatory response. 31,32 Investigation of this matter will be the focus of future research that may have implications regarding different mechanisms of lymphomagenesis at different anatomic locations, a previously unexplored area of DLBCL biology. For personal use only.…”