In peripheral T cells Rap1 has 2 opposing functions: one is to enhance integrin-mediated adhesion and the other is the regulation of Ras-dependent ERK activation. (A) T-cell activation requires multiple interactions with antigen-presenting cells (APCs). Antigen-dependent interactions are mediated by TCR recognition of antigen bound by the major histocompatibility complex (MHC) on the surface of APCs. Antigen-dependent signals downstream of TCR activate both Rap1 and Ras. Rap1 can enhance T-cell adhesion by stimulating the association of RapL with the α-chain of the integrin LFA-1, enhancing its affinity/avidity for ICAM. TCR activation of Ras and ERKs leads to the activation of multiple transcription factors, including the induction of the transcription factor Fos, which, in conjunction with other transcription factors (NFAT [nuclear factor of activated T cells] and nuclear factor κB [NFκB]), stimulates the transcription and production of IL-2, the major proliferative cytokine of activated T cells. TCR-dependent Rap1 activation antagonizes Ras signaling to ERKs, limiting IL-2 production. APCs express a transmembrane ligand B7 that binds 2 coreceptors, CD28 and CTLA-4, on T cells. Both CD28 and CTLA-4 regulate Rap1. CD28 augments signals from the TCR to IL-2 via multiple pathways, including ERKs shown here. CD28 inhibits TCR-dependent Rap1 activation, providing a mechanism for enhancing ERK-dependent IL-2 production. CTLA-4 antagonizes multiple stimulatory signals from the TCR to IL-2, including ERKs. In contrast to CD28, CTLA-4 activates Rap1, leading to down-regulation of ERK activity, providing a mechanism for the CTLA-4–dependent inhibition of IL-2 production. (B) The balance between the inhibition of ERK-dependent T-cell activation and the enhancement of LFA-dependent T-cell activation optimizes the T-cell response to antigen.