The role of CD4 and CD8 coreceptors in specifying the CD4 helper or CD8 cytotoxic T cell lineages during thymocyte development remains a controversial aspect of T cell developmental biology. Here we asked whether specification of the cytotoxic alpha-beta T cell lineage is determined by the CD8 protein or by the transcriptional control elements that regulate Cd8 gene expression, a concept we refer to as 'Coreceptor Imprinting'. To assess the possibility of coreceptor imprinting we knocked in Cd4 cDNA into the Cd8a gene locus and generated mutant mice in which CD4 protein expression is regulated by endogenous Cd8a transcriptional control elements. We reasoned that if the cytotoxic T cell lineage is specified by Cd8 gene transcriptional control elements (regardless of the coreceptor protein it encoded), then CD4 transcription from the Cd8 locus should promote the development of MHC class II-restricted thymocytes into the cytotoxic T cell lineage. Remarkably, unlike conventional MHCII-restricted CD4+ T cells that are helpers, MHCII-restricted CD4+ T cells generated in mice in which CD4 was exclusively encoded by the Cd8a gene were cytotoxic. Further, we provide evidence that transient termination of Cd8a gene-encoded CD4 transcription disrupts MHCII-specific TCR signals during positive selection permits a cytokine-dependent programming of the cytotoxic T cell fate. These results confirm the kinetic signaling model of CD4/CD8 lineage choice and demonstrate that specification of CD4 helper or CD8 cytotoxic alpha-beta T cell fate is dictated by the transcriptional control elements that regulate coreceptor gene expression, i.e. coreceptor imprinting.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Cancer Institute Division of Basic Sciences
Zip Code
Kimura, Motoko Y; Thomas, Julien; Tai, Xuguang et al. (2016) Timing and duration of MHC I positive selection signals are adjusted in the thymus to prevent lineage errors. Nat Immunol 17:1415-1423
Pobezinsky, Leonid A; Etzensperger, Ruth; Jeurling, Susanna et al. (2015) Let-7 microRNAs target the lineage-specific transcription factor PLZF to regulate terminal NKT cell differentiation and effector function. Nat Immunol 16:517-24
Takada, Kensuke; Van Laethem, Francois; Xing, Yan et al. (2015) TCR affinity for thymoproteasome-dependent positively selecting peptides conditions antigen responsiveness in CD8(+) T cells. Nat Immunol 16:1069-76
Tai, Xuguang; Singer, Alfred (2014) Basis of Treg development in the thymus. Cell Cycle 13:501-2
Katz, Gil; Pobezinsky, Leonid A; Jeurling, Susanna et al. (2014) T cell receptor stimulation impairs IL-7 receptor signaling by inducing expression of the microRNA miR-17 to target Janus kinase 1. Sci Signal 7:ra83
Mu, Jie; Tai, Xuguang; Iyer, Shankar S et al. (2014) Regulation of MHC class I expression by Foxp3 and its effect on regulatory T cell function. J Immunol 192:2892-903
Van Laethem, François; Saba, Ingrid; Tikhonova, Anastasia N et al. (2014) [Crucial role of CD4 and CD8 coreceptors in antigen recognition of ??T lymphocytes]. Med Sci (Paris) 30:511-3
Van Laethem, François; Tikhonova, Anastasia N; Pobezinsky, Leonid A et al. (2013) Lck availability during thymic selection determines the recognition specificity of the T cell repertoire. Cell 154:1326-41
Kimura, Motoko Y; Pobezinsky, Leonid A; Guinter, Terry I et al. (2013) IL-7 signaling must be intermittent, not continuous, during CD8? T cell homeostasis to promote cell survival instead of cell death. Nat Immunol 14:143-51
Tai, Xuguang; Erman, Batu; Alag, Amala et al. (2013) Foxp3 transcription factor is proapoptotic and lethal to developing regulatory T cells unless counterbalanced by cytokine survival signals. Immunity 38:1116-28

Showing the most recent 10 out of 24 publications