Timing and duration of MHC I positive selection signals are adjusted in the thymus to prevent lineage errors.
Major histocompatibility complex class I (MHC I) positive selection of CD8+T cells in the thymus requires that T cell antigen receptor (TCR) signaling end in time for cytokines to induce Runx3d, the CD8-lineage transcription factor. We examined the time required for these events and found that the overall duration of positive selection was similar for all CD8+thymocytes in mice, despite markedly different TCR signaling times. Notably, prolonged TCR signaling times were counter-balanced by accelerated Runx3d induction by cytokines and accelerated differentiation into CD8+T cells. Consequently, lineage errors did not occur except when MHC I-TCR signaling was so prolonged that the CD4-lineage-specifying transcription factor ThPOK was expressed, preventing Runx3d induction. Thus, our results identify a compensatory signaling mechanism that prevents lineage-fate errors by dynamically modulating Runx3d induction rates during MHC I positive selection.
Experimental Immunology Branch, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
Motoko Y
MY
Kimura
Experimental Immunology Branch, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
Julien
J
Thomas
Experimental Immunology Branch, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
Xuguang
X
Tai
Experimental Immunology Branch, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
Terry I
TI
Guinter
Experimental Immunology Branch, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
Miho
M
Shinzawa
Experimental Immunology Branch, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
Ruth
R
Etzensperger
Laboratory of Mammalian Genes and Development, Eunice Kennedy Schriver National Institute of Child Health and Human Development, US National Institutes of Health, Bethesda, Maryland, USA.
Zhenhu
Z
Li
Laboratory of Mammalian Genes and Development, Eunice Kennedy Schriver National Institute of Child Health and Human Development, US National Institutes of Health, Bethesda, Maryland, USA.
Paul
P
Love
Department of Immunology, Chiba University, Chiba, Japan.
Toshinori
T
Nakayama
Experimental Immunology Branch, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
Alfred
A
Singer
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D060966:Clonal Selection, Antigen-Mediated; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013950:Thymus Gland / Q000276:immunology*; D014157:Transcription Factors
D050677:Core Binding Factor Alpha 3 Subunit; D016207:Cytokines; D015395:Histocompatibility Antigens Class I; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; C493730:Runx3 protein, mouse; C497211:Zbtb7b protein, mouse
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