Developmental self-reactivity determines pathogenic Tc17 differentiation potential of naive CD8+ T cells in murine models of inflammation

Gil-Woo Lee, Young Ju Kim, Sung-Woo Lee, Hee-Ok Kim, Daeun Kim, Jiyoung Kim, You-Me Kim, Keunsoo Kang, Joon Haeng Rhee, Ik Joo Chung, Woo Kyun Bae, In-Jae Oh, Deok Hwan Yang and Jae-Ho Cho ()
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Gil-Woo Lee: Chonnam National University Medical School
Young Ju Kim: Chonnam National University Medical School
Sung-Woo Lee: Chonnam National University Medical School
Hee-Ok Kim: Selecxine
Daeun Kim: Selecxine
Jiyoung Kim: Korea Advanced Institute of Science and Technology
You-Me Kim: Korea Advanced Institute of Science and Technology
Keunsoo Kang: Dankook University
Joon Haeng Rhee: Chonnam National University Medical School
Ik Joo Chung: Chonnam National University Medical School
Woo Kyun Bae: Chonnam National University Medical School
In-Jae Oh: Chonnam National University Medical School
Deok Hwan Yang: Chonnam National University Medical School
Jae-Ho Cho: Chonnam National University Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract The differentiation of naive CD8+ T cells into effector cells is important for establishing immunity. However, the effect of heterogeneous naive CD8+ T cell populations is not fully understood. Here, we demonstrate that steady-state naive CD8+ T cells are composed of functionally heterogeneous subpopulations that differ in their ability to differentiate into type 17 cytotoxic effector cells (Tc17) in a context of murine inflammatory disease models, such as inflammatory bowel disease and graft-versus-host disease. The differential ability of Tc17 differentiation is not related to T-cell receptor (TCR) diversity and antigen specificity but is inversely correlated with self-reactivity acquired during development. Mechanistically, this phenomenon is linked to differential levels of intrinsic TCR sensitivity and basal Suppressor of Mothers Against Decapentaplegic 3 (SMAD3) expression, generating a wide spectrum of Tc17 differentiation potential within naive CD8+ T cell populations. These findings suggest that developmental self-reactivity can determine the fate of naive CD8+ T cells to generate functionally distinct effector populations and achieve immense diversity and complexity in antigen-specific T-cell immune responses.

Date: 2024
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DOI: 10.1038/s41467-024-47144-4

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