Mammalian Target of Rapamycin Complex 2 Controls CD8 T Cell Memory Differentiation in a Foxo1-Dependent Manner.

Upon infection, antigen-specific naive CD8 T cells are activated and differentiate into short-lived effector cells (SLECs) and memory precursor cells (MPECs). The underlying signaling pathways remain largely unresolved. We show that Rictor, the core component of mammalian target of rapamycin complex 2 (mTORC2), regulates SLEC and MPEC commitment. Rictor deficiency favors memory formation and increases IL-2 secretion capacity without dampening effector functions. Moreover, mTORC2-deficient memory T cells mount more potent recall responses. Enhanced memory formation in the absence of mTORC2 was associated with Eomes and Tcf-1 upregulation, repression of T-bet, enhanced mitochondrial spare respiratory capacity, and fatty acid oxidation. This transcriptional and metabolic reprogramming is mainly driven by nuclear stabilization of Foxo1. Silencing of Foxo1 reversed the increased MPEC differentiation and IL-2 production and led to an impaired recall response of Rictor KO memory T cells. Therefore, mTORC2 is a critical regulator of CD8 T cell differentiation and may be an important target for immunotherapy interventions.

Impact of the Femoral Head Position on Moment Arms in Total Hip Arthroplasty: A Parametric Finite Element Study.

BACKGROUND: Although the importance of accurate femoral reconstruction to achieve a good functional outcome is well documented, quantitative data on the effects of a displacement of the femoral center of rotation on moment arms are scarce. The purpose of this study was to calculate moment arms after nonanatomical femoral reconstruction. METHODS: Finite element models of 15 patients including the pelvis, the femur, and the gluteal muscles were developed. Moment arms were calculated within the native anatomy and compared to distinct displacement of the femoral center of rotation (leg lengthening of 10 mm, loss of femoral offset of 20%, anteversion ±10°, and fixed anteversion at 15°). Calculations were performed within the range of motion observed during a normal gait cycle. RESULTS: Although with all evaluated displacements of the femoral center of rotation, the abductor moment arm remained positive, some fibers initially contributing to extension became antagonists (flexors) and vice versa. A loss of 20% of femoral offset led to an average decrease of 15% of abductor moment. Femoral lengthening and changes in femoral anteversion (±10°, fixed at 15°) led to minimal changes in abductor moment arms (maximum change of 5%). Native femoral anteversion correlated with the changes in moment arms induced by the 5 variations of reconstruction. CONCLUSION: Accurate reconstruction of offset is important to maintaining abductor moment arms, while changes of femoral rotation had minimal effects. Patients with larger native femoral anteversion appear to be more susceptible to femoral head displacements.