# Unraveling CD8 lineage decisions reveals that functionally distinct CD8+ T cells are selected by different MHC-I thymic peptides

## TL;DR

This study shows that different MHC-I peptides in the thymus determine the functional fate of CD8+ T cells during their development.

## Contribution

The study introduces a novel mouse model to show how MHC-I peptide distribution in the thymus influences CD8+ T cell lineage decisions.

## Key findings

- β5t-peptides in the thymic cortex select cytotoxic CD8+ T cells.
- Nonβ5t-peptides throughout the thymus select helper or innate memory CD8+ T cells.
- Peptide-specific signaling duration determines CD8+ T cell function.

## Abstract

Thymocytes signaled by T cell antigen receptors to undergo positive selection acquire different functional fates while migrating through the thymus, but how this occurs remains uncertain. We now report that encoding CD8 co-receptors in both Cd4 and Cd8 gene loci modulates major histocompatibility complex (MHC-I) class I T cell antigen receptor signaling duration to generate all potential CD8+ T cell subsets. Strikingly, such mice revealed that functionally different CD8+ T cells are selected by different MHC-I thymic peptides. Thymocytes signaled by β5t-peptides produced by thymoproteasomes exclusively expressed in the thymic cortex invariably become cytotoxic CD8+ T cells indicating their signaling ceases when thymocytes leave the cortex; whereas thymocytes signaled by nonβ5t-peptides expressed throughout the thymus become either helper or innate memory CD8+ T cells because their signaling persists or recurs outside the cortex. Thus, it is because of their different thymic distributions that different MHC-I peptides select functionally different CD8+ T cells, integrating peptide specificity and CD8+ T cell function during positive selection and thymocyte migration.

Shinzawa et al. developed CD8Dual mice that express CD8 co-receptors from both Cd4 and Cd8 gene loci. Using this model they find that thymic distribution of major histocompatibility complex class I peptides influences lineage commitment and CD8+ T cell function.