Phosphatidylinositol 3-kinase regulates the CD4/CD8 T cell differentiation ratio.
The signaling pathways that control T cell differentiation have only begun to be elucidated. Using T cell lines, it has been shown that class IA phosphatidylinositol 3-kinase (PI3K), a heterodimer composed of a p85 regulatory and a p110 catalytic subunit, is activated after TCR stimulation. Nonetheless, the contribution of p85/p110 PI3K isoforms in T cell development has not been described. Mice deficient in the other family of class I PI3K, p110gamma, which is regulated by G protein-coupled receptors, exhibit reduced thymus size. Here we examine T cell development in p110gamma-deficient mice and in mice expressing an activating mutation of the p85 regulatory subunit, p65(PI3K), in T cells. We show that p110gamma-deficient mice have a partial defect in pre-TCR-dependent differentiation, which is restored after expression of the p65(PI3K) activating mutation. Genetic alteration of both PI3K isoforms also affects positive selection; p110gamma deletion decreased and p65(PI3K) expression augmented the CD4(+)/CD8(+) differentiation ratio. Finally, data are presented showing that both PI3K isoforms influenced mature thymocyte migration to the periphery. These observations underscore the contribution of PI3K in T cell development, as well as its implication in determining the CD4(+)/CD8(+) T cell differentiation ratio in vivo.
Rodríguez-Borlado
Luis
L
Department of Immunology and Oncology, Centro Nacional de Biotecnología, Universidad Autónoma, Cantoblanco, Madrid, Spain.
Barber
Domingo F
DF
Hernández
Carmen
C
Rodríguez-Marcos
Miguel A
MA
Sánchez
Arsenio
A
Hirsch
Emilio
E
Wymann
Matthias
M
Martínez-A
Carlos
C
Carrera
Ana C
AC
D000818:Animals; D015704:CD4 Antigens / Q000096:biosynthesis; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D016827:CD8 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D007527:Isoenzymes / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D019076:Transgenes / Q000276:immunology
D015704:CD4 Antigens; D016827:CD8 Antigens; D000949:Histocompatibility Antigens Class II; C024138:I-E-antigen; D007527:Isoenzymes; D011948:Receptors, Antigen, T-Cell; D019869:Phosphatidylinositol 3-Kinases