A narrow T cell receptor repertoire instructs thymic differentiation of MHC class Ib–restricted CD8+ regulatory T cells
Hye-Jung Kim, … , Jamil R. Azzi, Harvey Cantor
Hye-Jung Kim, … , Jamil R. Azzi, Harvey Cantor
Published November 7, 2023
Citation Information: J Clin Invest. 2024;134(1):e170512. https://doi.org/10.1172/JCI170512.
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A narrow T cell receptor repertoire instructs thymic differentiation of MHC class Ib–restricted CD8+ regulatory T cells

Abstract

Although most CD8+ T cells are equipped to kill infected or transformed cells, a subset may regulate immune responses and preserve self-tolerance. Here, we describe a CD8 lineage that is instructed to differentiate into CD8 T regulatory cells (Tregs) by a surprisingly restricted set of T cell receptors (TCRs) that recognize MHC-E (mouse Qa-1) and several dominant self-peptides. Recognition and elimination of pathogenic target cells that express these Qa-1–self-peptide complexes selectively inhibits pathogenic antibody responses without generalized immune suppression. Immunization with synthetic agonist peptides that mobilize CD8 Tregs in vivo efficiently inhibit antigraft antibody responses and markedly prolong heart and kidney organ graft survival. Definition of TCR-dependent differentiation and target recognition by this lineage of CD8 Tregs may open the way to new therapeutic approaches to inhibit pathogenic antibody responses.

Authors

Hye-Jung Kim, Hidetoshi Nakagawa, John Y. Choi, Xuchun Che, Andrew Divris, Qingshi Liu, Andrew E. Wight, Hengcheng Zhang, Anis Saad, Zhabiz Solhjou, Christa Deban, Jamil R. Azzi, Harvey Cantor

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Figure 2

Qa-1–dependent differentiation of FL9 T cells.

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Qa-1–dependent differentiation of FL9 T cells. (A) Frequency of Tg TCR+ ...
(A) Frequency of Tg TCR+ cells in the TCR+ thymic cells in OT-I– or FL9.2 TCR Tg mice (Va2+Vβ5+ for OT-I and Vα3.2+Vβ5+ for FL9 T cells) and levels of Helios expression. (B) Frequency of Tg TCR+ cells in the TCR+ splenic cells in OT-I or FL9 TCR Tg mice and levels of Helios and Ly49 expression. (C) Frequency of FL9 TCR Tg T cells in the TCR+ thymic cells in WT or Qa-1–/–.FL9 TCR Tg mice. Frequency of FL9 Tg T cells (Vα3.2+Vβ5+) in the total thymocytes is shown in graph (right). (D) Frequency of Vα3.2+Vβ5+ T cells in TCRβ+ spleen cells from FL9.2 TCR Tg mice on Qa-1–WT and –KO backgrounds (at 8 weeks old). Representative FACS plots for the detection of Vα3.2+Vβ5+ cells in spleen are shown (left panel). (E) Expression of CD44 and NKG2D by FL9.2 T cells in spleens of WT.FL9.2 TCR Tg and Qa-1–/–.FL9.2 TCR Tg mice. Representative FACS plots for NKG2D+CD44+ cells in the spleens of FL9.2 TCR Tg mice are shown on the left. (F) Expression of Ki67 by FL9.2 T cells in the LNs of WT.FL9.2 TCR Tg and Qa-1–/–.FL9.2 TCR Tg mice. (G) CFSE-labeled FL9.2 T cells developed in Qa-1–WT or Qa-1–KO mice were transferred into irradiated (800 rads) Qa-1–WT, Qa-1–KO and D227K-KI adoptive hosts. Seven days after transfer, Qa-1–WT or Qa-1–KO FL9.2 T cells were recovered from spleens of adoptive hosts. Numbers of FL9.2 T cells in the spleens of adoptive hosts are shown. (H) Percentage of Qa-1 WT FL9.2 T cells that undergo more than 3 divisions in Qa-1–WT, Qa-1–KO and D227K-KI hosts. Mean ± SEM is indicated. ****P < 0.0001, ***P < 0.001, **P < 0.01, *P < 0.05.