TCR Affinity for In Vivo Peptide-Induced Thymic Positive Selection Fine-Tunes TCR Responsiveness of Peripheral CD8+ T Cells

Abstract

The affinity for TCR interactions with self-peptide/MHC complexes (pMHC) in the thymus critically affects immature thymocytes that newly express TCRs. Previous fetal thymus organ culture experiments have indicated that difference in the affinity for thymic TCR/pMHC interactions not only determines thymocyte fate between positive and negative selection, but also affects Ag responsiveness of positively selected thymocytes. In the current study, we examined whether TCR/pMHC affinity during positive selection in the thymus would further affect Ag responsiveness of mature T cells in the periphery. To do so, OVA peptide variants were in vivo administered to TAP1-deficient OT-I/TCR-transgenic mice in which T cell development was otherwise arrested at CD4 + CD8 + thymocytes because of the lack of self-pMHC presentation in thymic APCs. We found that a group of peptide variants induced the transient generation of OT-I CD8 + T cells in the thymus and the periphery. We also noticed that the affinity threshold for positive and negative selection detected in adult mice in vivo was higher than that measured in fetal thymus organ culture experiments in vitro. Interestingly, we further found that the affinity for positively selecting peptides proportionally affected TCR responsiveness of peripheral naive CD8 + T cells. These results indicate that in vivo administration of a peptide can promote T cell selection in the thymus and the affinity for TCR/pMHC interaction during positive selection fine-tunes Ag responsiveness of peripheral T cells.

A stepwise and digital pattern of RSK phosphorylation determines the outcome of thymic selection

“… 62 Given that the effects of OVA peptide ligands in FTOC differ to some extent from those in adult mice, additional factors may also play a role in thymic selection in vivo . 63 In addition, the signals that accompany positive and negative selection in vivo or in situ appear to be different than what is observed after in vitro stimulation with tetramers. 64 However, TCR affinity is a key factor that distinguishes the fates of thymocytes between positive and negative selection, and our finding in this paper using tetramer stimulation in vitro appears to recapitulate at least this aspect of the process.…”

Assembling the thymus medulla: Development and function of epithelial cell heterogeneity

“…A key role of cTEC is to present selfpeptide/MHC complexes against which developing DP thymocytes are able to test their randomly generated αβTCRs. [7][8][9] Here, DP thymocytes capable of self-peptide/MHC recognition are rescued from cell death through the process of positive selection (recently reviewed here [10] ). DP thymocytes that are able to successfully recognise αβTCRself-peptide/MHC complexes presented by cTEC downregulate either CD4 or CD8 co-receptor to become single positive (SP) thymocytes dependent on the capacity of their TCR to recognise self-peptide loaded MHC class I or MHC class II molecules respectively.…”