| First Author | Xing Y | Year | 2013 |
| Journal | Proc Natl Acad Sci U S A | Volume | 110 |
| Issue | 17 | Pages | 6979-84 |
| PubMed ID | 23569244 | Mgi Jnum | J:196156 |
| Mgi Id | MGI:5486612 | Doi | 10.1073/pnas.1222244110 |
| Citation | Xing Y, et al. (2013) Thymoproteasome subunit-beta5T generates peptide-MHC complexes specialized for positive selection. Proc Natl Acad Sci U S A 110(17):6979-84 |
| abstractText | Cortical thymic epithelial cells (cTECs) express a unique thymoproteasome subunit-beta5T that plays an essential role in the development of CD8 T cells. In contrast, the immunoproteasome subunit-beta5i 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 beta5T, by generating beta5t(5i) knockin mice, in which beta5i replaced beta5T in cTECs. When such animals were crossed to beta5i(-/-) mice, beta5i was exclusively expressed in cTECs, whereas beta5 was expressed in other cells. However, this mouse did not support normal positive selection, suggesting that beta5T generates peptides that are intrinsically better for positive selection (i.e., beta5i could not replace beta5T) 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 beta5T 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, naive T-cell clones. |
