Gads is an important regulator in T cell receptor (TCR)-mediated Ca2+ mobilization. We investigated the role of Gads in peripheral CD8+ T cell proliferation, using the MHC Class I-restricted ovalbumin-specific TCR transgenic mouse line (OT-I) on either the Gads+/+ or Gads-/- genetic background. We found that the Gads deficiency impaired TCR-mediated proliferation both in vitro and in vivo. This defect was most evident when low doses of cognate antigen (SIINFEKL) or altered peptide ligands (APLs) with lower affinity for the OT-I TCR were used as stimuli. However, the requirement for Gads in the proliferation of CD8+ T cells could be overcome by stimulating cells with high doses of SIINFEKL or APLs. The defect of Gads-/- CD8+ T cells in proliferation was caused by both impaired survival and by delayed entry into the cell cycle. We conclude that Gads regulates the signaling threshold through the TCR by promoting survival and cell cycle entry of CD8+ T cells. This research is supported by NIH grant P20 RR016443.