Classical MHC expression by DP thymocytes impairs the selection of non-classical MHC restricted innate-like T cells

Hristo Georgiev,Matthew A Huggins,Changwei Peng,Stephen C Jameson,Kristin A Hogquist

doi:10.1038/s41467-021-22589-z

Hristo Georgiev, Matthew A Huggins + Show 3 more

Open Access

https://doi.org/10.1038/s41467-021-22589-z

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Abstract

Conventional T cells are selected by peptide-MHC expressed by cortical epithelial cells in the thymus, and not by cortical thymocytes themselves that do not express MHC I or MHC II. Instead, cortical thymocytes express non-peptide presenting MHC molecules like CD1d and MR1, and promote the selection of PLZF+ iNKT and MAIT cells, respectively. Here, we report an inducible class-I transactivator mouse that enables the expression of peptide presenting MHC I molecules in different cell types. We show that MHC I expression in DP thymocytes leads to expansion of peptide specific PLZF+ innate-like (PIL) T cells. Akin to iNKT cells, PIL T cells differentiate into three functional effector subsets in the thymus, and are dependent on SAP signaling. We demonstrate that PIL and NKT cells compete for a narrow niche, suggesting that the absence of peptide-MHC on DP thymocytes facilitates selection of non-peptide specific lymphocytes.

Highlights

Conventional T cells are selected by peptide-major histocompatibility complex (MHC) expressed by cortical epithelial cells in the thymus, and not by cortical thymocytes themselves that do not express MHC I or MHC II
Conventional CD4 and CD8 T-cell development was not compromised in these mice, the development of invariant natural killer T (iNKT) cells was reduced, indicating that PLZF+ innate-like (PIL) T cells and iNKT cells compete for a limited thymic niche. These results suggest that the absence of peptidepresenting MHC class I molecules on DP thymocytes is a consequence of not expressing Nlrc[5] and functions to facilitate the development of non-peptide-specific lymphocyte subsets such as iNKT cells
It was previously shown that the expression of MHC II on DP thymocytes promotes the development of MHC II-restricted thymocyte-selected CD4 T cells (T-CD4) with an NKT-like phenotype[21,22,24,29]

Summary

Introduction

Conventional T cells are selected by peptide-MHC expressed by cortical epithelial cells in the thymus, and not by cortical thymocytes themselves that do not express MHC I or MHC II. Cortical thymocytes express non-peptide presenting MHC molecules like CD1d and MR1, and promote the selection of PLZF+ iNKT and MAIT cells, respectively. 1234567890():,; The study of innate-like T cells, namely invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells, and γδ T cells, is rapidly expanding and gaining interest Defined by their phenotype, innate-like T cells bear functional T-cell receptor (TCR) rearrangements, yet acquire a memory phenotype during development, and quickly respond to stimulation without undergoing extensive clonal expansion[1,2]. Conventional αβ T cells undergo positive and negative selection by thymic epithelial cells (TECs) presenting peptide antigens by classical class I and II major histocompatibility complex (MHC) molecules. In both transgenic mice, MHC II was expressed on DP thymocytes This lead to an expansion of thymocyte-selected PLZF+ T cells with an innate-like phenotype similar to iNKT cells[23,24]

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