Thymoproteasome subunit-?5T generates peptide-MHC complexes specialized for positive selection.

ABSTRACT: Cortical thymic epithelial cells (cTECs) express a unique thymoproteasome subunit-?5T that plays an essential role in the development of CD8 T cells. In contrast, the immunoproteasome subunit-?5i is expressed in other thymic antigen-presenting cells (APCs). The thymoproteasome may generate peptides that are specialized for positive selection, or it may simply serve to generate peptides that are distinct from other APCs that cause negative selection, thereby promoting an overall larger number of surviving clones to mature and function in the immune system. To distinguish these models, we genetically engineered mice to express distinct peptide repertoires in cTECs vs. other APCs without expressing ?5T, by generating ?5t(5i) knockin mice, in which ?5i replaced ?5T in cTECs. When such animals were crossed to ?5i(-/-) mice, ?5i was exclusively expressed in cTECs, whereas ?5 was expressed in other cells. However, this mouse did not support normal positive selection, suggesting that ?5T generates peptides that are intrinsically better for positive selection (i.e., ?5i could not replace ?5T) and not merely because these peptides are distinct from peptides presented by other APCs. Finally, using an Nur77(GFP) reporter, we show that the T cells generated in the absence of ?5T have higher reactivity to self, generating predominantly CD44(hi) memory phenotype peripheral CD8(+) T cells. Altogether, our results suggest that the thymoproteasome supports positive selection by generating peptides that are optimized for the selection of weakly self-reactive, naïve T-cell clones.

SUBMITTER: Xing Y 

PROVIDER: S-EPMC3637736 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature