Coreceptor gene imprinting governs thymocyte lineage fate.
Immature thymocytes are bipotential cells that are signalled during positive selection to become either helper- or cytotoxic-lineage T cells. By tracking expression of lineage determining transcription factors during positive selection, we now report that the Cd8 coreceptor gene locus co-opts any coreceptor protein encoded within it to induce thymocytes to express the cytotoxic-lineage factor Runx3 and to adopt the cytotoxic-lineage fate, findings we refer to as 'coreceptor gene imprinting'. Specifically, encoding CD4 proteins in the endogenous Cd8 gene locus caused major histocompatibility complex class II-specific thymocytes to express Runx3 during positive selection and to differentiate into CD4(+) cytotoxic-lineage T cells. Our findings further indicate that coreceptor gene imprinting derives from the dynamic regulation of specific cis Cd8 gene enhancer elements by positive selection signals in the thymus. Thus, for coreceptor-dependent thymocytes, lineage fate is determined by Cd4 and Cd8 coreceptor gene loci and not by the specificity of T-cell antigen receptor/coreceptor signalling. This study identifies coreceptor gene imprinting as a critical determinant of lineage fate determination in the thymus.
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Stanley
S
Adoro
Thomas
T
McCaughtry
Batu
B
Erman
Amala
A
Alag
François
F
Van Laethem
Jung-Hyun
JH
Park
Xuguang
X
Tai
Motoko
M
Kimura
Lie
L
Wang
Alex
A
Grinberg
Masato
M
Kubo
Remy
R
Bosselut
Paul
P
Love
Alfred
A
Singer
D000818:Animals; D015704:CD4 Antigens / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D016827:CD8 Antigens / Q000235:genetics*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology*; D019070:Cell Lineage / Q000235:genetics; D060966:Clonal Selection, Antigen-Mediated; D050677:Core Binding Factor Alpha 3 Subunit / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000502:physiology; D004274:DNA, Recombinant / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics; D055879:Gene Knock-In Techniques; D005813:Genes, Synthetic; D038041:Lymphopoiesis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000166:cytology*; D060168:Thymocytes / Q000166:cytology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
D015704:CD4 Antigens; D016827:CD8 Antigens; D050677:Core Binding Factor Alpha 3 Subunit; D016207:Cytokines; D004274:DNA, Recombinant; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; C493730:Runx3 protein, mouse; C491590:Socs1 protein, mouse; C497211:Zbtb7b protein, mouse