Sin1 regulates Treg-cell development but is not required for T-cell growth and proliferation.
Mammalian Sin1 plays key roles in the regulation of mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling. Sin1 is an essential component of mTOR complex 2 (mTORC2). The functions of Sin1 and mTORC2 remain largely unknown in T cells. Here, we investigate Sin1 function in T cells using mice that lack Sin1 in the hematopoietic system. Sin1 deficiency blocks the mTORC2-dependent Akt phosphorylation in T cells during development and activation. Sin1-deficient T cells exhibit normal thymic cellularity and percentages of double-negative, double-positive, and single-positive CD4(+) and CD8(+) thymocytes. Sin1 deficiency does not impair T-cell receptor (TCR) induced growth and proliferation. Sin1 appears dispensable for in vitro CD4(+) helper cell differentiation. However, Sin1 deficiency results in an increased proportion of Foxp3(+) natural T-regulatory (nTreg) cells in the thymus. The TGF-β-dependent differentiation of CD4(+) T cells in vitro is enhanced by the inhibition of mTOR but not by loss of Sin1 function. Our results reveal that Sin1 and mTORC2 are dispensable for the development and activation of T cells but play a role in nTreg-cell differentiation.
Department of Immunobiology and Vascular Biology and Therapeutic Program, Yale School of Medicine, New Haven, Connecticut 06519, USA.
Xing
X
Chang
Adam S
AS
Lazorchak
Dou
D
Liu
Bing
B
Su
D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D008213:Lymphocyte Activation; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D011506:Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000502:physiology; D048868:Adaptor Proteins, Signal Transducing
D002352:Carrier Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D011948:Receptors, Antigen, T-Cell; D058570:TOR Serine-Threonine Kinases; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C504923:Crtc2 protein, mouse; C561937:Mapkap1 protein, mouse; D048868:Adaptor Proteins, Signal Transducing; C546843:mTOR protein, mouse