CTLA-4 is a CD28 homolog with high affinity for B7-1/2. While the CD28:B7-1/2 interaction serves as a co-stimulatory signal for T cell proliferation and activation, the CTLA-4:B7-1/2 binding acts as a co-inhibitory signal to thwart early T cell activation. CTLA-4 knockout mice provided supporting evidence that CTLA-4 is an essential “brake” on T cells to restrain immune responses. The expression of CTLA-4 is subject to tight regulation through several mechanisms. First, CTLA4 mRNA expression is regulated by a number of transcription factors, such as NFAT  and FoxP3. Second, cellular localization of CTLA-4 also controls CTLA-4 signaling. In resting T cells, CTLA-4 localizes intracellularly, however, the exocytosis of CTLA-4 containing vesicles and subsequent presentation of CTLA-4 on immunological synapses are induced upon T cell stimulation.