Lck is a central node in the T cell receptor signaling pathway. (A) Following T cell receptor (TCR)/CD3 complex ligation, Lck phosphorylation sites (inhibitory Tyr505 and activatory Tyr394) regulate Lck activity. The phosphorylation of immunotyrosine-based activating motifs (ITAMs) by Lck induces recruitment of other kinases and leads to T cell activation. Phosphorylation of Lck is regulated positively by CD45 and negatively by C-terminal Src kinase (Csk), itself regulated by phosphoprotein associated with GEMs (PAG), and Src homology 2 domain-containing protein tyrosine-phosphatase 1 (SHP-1). The regulation of phosphatases such as SHP-1 is strongly influenced by oxidative stress (reactive oxygen species) and the Nrf2 pathway. (B) Nrf2 quantification in resting and activated (anti-CD3/CD28) T cell cytoplasm in young versus older individuals is shown (a representative blot is shown). In addition, there are other regulatory mechanisms that function rapidly as negative feedback loops from the TCR signalosome itself . One of these involves phosphatases, especially SHP-1 . Reduction of SHP-1 activity upon stimulation lowers the threshold for TCR activation. It seems that under weak stimulation activated Lck associates with and phosphorylates SHP-1, the activity of which then becomes reduced, but not sufficiently to allow full signaling to occur. Thus, under strong stimulation, Lck activity would increase or become sufficient when SHP-1 activity is reduced very early in the signaling cascade. In turn, when the signal weakens, SHP-1 activity increases and consequently downregulates Lck activity . Many other negative feedback mechanisms are in operation during the early and late phases of TCR signaling .