T cell receptor (TCR) engagement leads to actin polymerization at the site of T cell contact with antigen-presenting cells. Here we have studied the dynamic activity of proteins involved in regulating actin polymerization in live T cells after activation. Two such adaptor proteins, Nck and the Wiskott-Aldrich syndrome protein (WASp), were recruited to the TCR during initial T cell activation, where they colocalized with the tyrosine kinase Zap70. The recruitment of Nck and WASp depended on TCR-induced tyrosine phosphorylation and the LAT and SLP-76 adaptors. Nck and WASp migrated peripherally and accumulated at an actin-rich circumferential ring. Thus, actin polymerization regulated by the TCR begins at the TCR. Molecules recruited to the TCR regulate actin polymerization and this process drives plasma membrane movement and cellular spreading.

Background and Aims: Patients with chronic hepatitis C virus (HCV) infection display great variability in disease activity and progression. While virus-specific adaptive immune responses have been extensively characterized and found to be impaired in chronic hepatitis C, the role of innate immune responses in disease activity and progression of chronic hepatitis C is not well understood.

Background & Aims Mathematical modeling of hepatitis C virus (HCV) kinetics indicated that the cellular immune response contribute to interferon (IFN)-induced clearance of HCV. We investigated a potential role of natural killer (NK) cells in this process. Methods Phenotype and function of blood and liver NK cells were studied during the first 12 weeks of treatment with pegylated IFN-alfa and ribavirin, the time period used to define the early virological response. Results Within hours of treatment initiation, NK cells of patients that had an early virological response increased expression of the activating receptors NKG2D, NKp30, and CD16; they decreased expression of NKG2C and 2B4, along with the inhibitory receptors SIGLEC7 and NKG2A, resulting in NK cell activation. NK cell cytotoxicity, measured by degranulation and TRAIL production, peaked after 24 h (P<.01), concomitant with an increase in alanine aminotransferase levels (P<.05), whereas IFN-g production decreased within 6 h and did not recover for more than 4 weeks (P<.05). NK cells from liver biopsies taken 6 h after treatment initiation had increased numbers of cytotoxic CD16+ NK cells (P<.05) and a trend towards increased production of TRAIL. Degranulation of peripheral blood NK cells correlated with the treatment-induced, first phase decreases in viral load (P<.05) and remained higher in early virological responders than in nonresponders for weeks. Conclusions IFN activates NK cells early after treatment is initiated. Their cytotoxic function, in particular, is strongly induced, which correlates to the virologic response. Therefore, NK cell activation indicates responsiveness to IFN-g–based treatment and indicates the involvement of the innate immune cells in viral clearance.