Runx3 regulates integrin alpha E/CD103 and CD4 expression during development of CD4-/CD8+ T cells.
During thymic T cell development, immature CD4+CD8+ double-positive (DP) thymocytes develop either into CD4+CD8- Th cells or CD4-CD8+ CTLs. Differentially expressed primary factors inducing the fate of these cell types are still poorly described. The transcription factor Runx3/AML-2 Runx, runt [corrected] dominant factor; AML, acute myeloid leukemia is expressed specifically during the development of CD8 single-positive (SP) thymocytes, where it silences CD4 expression. Deletion of murine Runx3 results in a reduction of CD8 SP T cells and concomitant accumulation of CD4+CD8+ T cells, which cannot down-regulate CD4 expression in the thymus and periphery. In this study we have investigated the role of Runx3 during thymocyte development and CD4 silencing and have identified integrin alpha(E)/CD103 on CD8 SP T cells as a new potential target gene of Runx3. We demonstrate that Runx3 is necessary not only to repress CD4, but also to induce CD103 expression during development of CD8 SP T cells. In addition, transgenic overexpression of Runx3 reduced CD4 expression during development of DP thymocytes, leading to a reduced number of CD4 SP thymocytes and an increased number of CD8 SP thymocytes. This reversal is not caused by redirection of specific MHC class II-restricted cells to the CD8 lineage. Overexpression of Runx3 also up-regulated CD103 expression on a subpopulation of CD4 SP T cells with characteristics of regulatory T cells. Thus, Runx3 is a main regulator of CD4 silencing and CD103 induction and thus contributes to the phenotype of CD8 SP T cells during thymocyte development.
Grueter
Baerbel
B
Institute of Molecular Biology (Cancer Research), University of Essen, Medical School, Essen, Germany.
Petter
Michaela
M
Egawa
Takeshi
T
Laule-Kilian
Kirsten
K
Aldrian
Christine J
CJ
Wuerch
Andreas
A
Ludwig
Yvonne
Y
Fukuyama
Hidehiro
H
Wardemann
Hedda
H
Waldschuetz
Ralph
R
Möröy
Tarik
T
Taniuchi
Ichiro
I
Steimle
Viktor
V
Littman
Dan R
DR
Ehlers
Marc
M
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis*; D015704:CD4 Antigens / Q000096:biosynthesis* / Q000235:genetics; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016827:CD8 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D050677:Core Binding Factor Alpha 3 Subunit; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D020868:Gene Silencing; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D039001:Integrin alpha Chains / Q000096:biosynthesis*; D007694:Killer Cells, Natural / Q000166:cytology; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D013945:Thymoma / Q000235:genetics / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology
D015703:Antigens, CD; D015704:CD4 Antigens; D016827:CD8 Antigens; D050677:Core Binding Factor Alpha 3 Subunit; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D000949:Histocompatibility Antigens Class II; D039001:Integrin alpha Chains; C493730:Runx3 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C091367:alpha E integrins