Pre-T cell receptor self-MHC sampling restricts thymocyte dedifferentiation

Area of Science:

• Immunology
• Developmental Biology
• Cellular Biology

Background:

• T cell development requires distinguishing self from non-self in the thymus.
• Pre-T cell receptor (preTCR) signaling is a critical checkpoint for αβ T cell lineage development.
• PreTCRs on double-negative thymocytes interact with peptide-MHC (pMHC) on stromal cells.

Purpose of the Study:

• To investigate the consequences of distinct preTCR-pMHC interactions on thymocyte progression.
• To analyze thymocyte transcriptional programming and differentiation in response to pMHC presence or absence.

Main Methods:

• Utilized synchronized fetal thymic progenitor cultures with and without pMHC-expressing stroma.
• Employed single-cell transcriptomics at key thymocyte developmental transitions.
• Examined MHC-knockout mouse models to assess in vivo thymocyte progression.

Main Results:

• Absence of preTCR-pMHC interactions on MHC-negative stroma induced deviant transcriptional programming and dedifferentiation.
• Highly proliferative double-negative and double-positive thymocyte subsets emerged, resembling malignancies.
• Compensatory MHC class Ib upregulation partially rescued in vivo progression, but thymic tumors could develop with age.

Conclusions:

• PreTCR-pMHC interactions are essential for normal thymocyte differentiation and proliferation, preventing dedifferentiation.
• These interactions limit cellular plasticity, thereby safeguarding against developmental vulnerabilities and potential oncogenesis.
• Failure of preTCR-pMHC signaling creates developmental vulnerabilities that can lead to T cell lymphoblastic and myeloid malignancies.