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.