CD8 T cell tolerance results from eviction of immature autoreactive cells from the thymus

CD8 T cell tolerance is thought to result from clonal deletion of autoreactive thymocytes before they differentiate into mature CD8 T cells in the thymus. However, we report that, in mice, CD8 T cell tolerance instead results from premature thymic eviction of immature autoreactive CD8 thymocytes int...

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Published inScience (American Association for the Advancement of Science) Vol. 382; no. 6670; pp. 534 - 541
Main Authors Badr, Mohamed Elsherif, Zhang, Zhongmei, Tai, Xuguang, Singer, Alfred
Format Journal Article
LanguageEnglish
Published United States The American Association for the Advancement of Science 03.11.2023
Subjects
Animals
CD4 antigen
CD8 antigen
CD8-Positive T-Lymphocytes - immunology
Clonal Deletion
Clonal selection
Epithelial cells
Epithelium
Female
Immunological tolerance
Lymphocytes
Lymphocytes T
Male
Mice
Mice, Transgenic
Peripheral Tolerance
Receptors, Antigen, T-Cell - genetics
Receptors, Antigen, T-Cell - metabolism
T cell receptors
Thymocytes
Thymus
Thymus Gland - cytology
Thymus Gland - immunology
Transcription Factors - metabolism
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Summary:CD8 T cell tolerance is thought to result from clonal deletion of autoreactive thymocytes before they differentiate into mature CD8 T cells in the thymus. However, we report that, in mice, CD8 T cell tolerance instead results from premature thymic eviction of immature autoreactive CD8 thymocytes into the periphery, where they differentiate into self-tolerant mature CD8 T cells. Premature thymic eviction is triggered by T cell receptor (TCR)-driven down-regulation of the transcriptional repressor Gfi1, which induces expression of sphingosine-1-phosphate receptor-1 (S1P1) on negatively selected immature CD8 thymocytes. Thus, premature thymic eviction is the basis for CD8 T cell tolerance and is the mechanism responsible for the appearance in the periphery of mature CD8 T cells bearing autoreactive TCRs that are absent from the thymus.
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Author contributions: M.E.B. conceptualized the study, designed and performed experiments, analyzed data, and wrote the manuscript. Z.Z. and X.T. provided resources and performed experiments. A.S. conceptualized and supervised the study and wrote the manuscript.
ISSN:0036-8075
1095-9203
1095-9203
DOI:10.1126/science.adh4124