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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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Research Article Immunology Article has an altmetric score of 46

A narrow T cell receptor repertoire instructs thymic differentiation of MHC class Ib–restricted CD8+ regulatory T cells

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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 3

FL9 Tg CD8 T cells recognize and suppress activated CD4 T cells.

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FL9 Tg CD8 T cells recognize and suppress activated CD4 T cells.
(A) in ...
(A) in vitro, conA-stimulated CD4 cells from WT B6, Qa-1.D227K–KI, KbDb-KO and ERAAP-KO mice were cocultured with FL9.2 T cells isolated from FL9.2 TCR Tg mice. WT CD4 cells loaded with the FL9 peptide were used as a positive control. After 20 hours, CD69 expression on FL9 Tg T cells were measured as a readout of TCR stimulation. (B) In vivo, WT or D227K mice were immunized with OT-II peptides in CFA. After 7 days, CD4 (CD4+CD25–) cells were isolated from immunized mice and transferred into WT B6 hosts with or without FL9 TCR Tg T cells followed by immunization with OT-II/CFA. Detection of I-Ab/Ova323-339-specific CD4 T cells in the spleen of hosts by I-Ab/Ova323-339 tets (upper). Percent and numbers of I-Ab/Ova323-339 tet+ (upper) and I-Ab/Ova323-339 tet– activated (lower) CD4 cells recovered from adoptive hosts (middle and right). (C) Qa-1 expression by I-Ab/Ova323-339 tet+ and tet– CD4 cells. (D) WT B6 and D227K mice were immunized with Ova/CFA and injected with isotype or anti-Vα3.2 antibodies on day 0, before boosting on day 8 with Ova/IFA along with antibody injection. Frequency of I-Ab/Ova323-339 tet+ CD4 cells in blood were assessed on day 15. ****P < 0.0001, ***P < 0.001, **P < 0.01, *P < 0.05.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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