Communication between the nervous and immune systems is critical for regulating the immune response. Neuropeptides have been observed to exert modulatory effects on many different lymphocyte subsets. In mouse models, we found peripheral T cells expressed a set of 26 neurotransmitter receptors and exhibited distinct patterns across T cell subsets. The Vasoactive Intestinal Peptide receptor (VIPR1) had an intriguing pattern with high expression in naïve peripheral CD4 T cells and none in Tregs. Upon T cell receptor (TCR) stimulation, VIPR1 expression rapidly declines, suggesting endogenous VIP primarily affects resting naïve T cells. Functionally, treatment with VIP dampened the early activation of naïve T cells, as measured by reductions in proliferative responses and IL-2 secretion in response to antigenic stimulation. Mechanistically, VIP-exposure directly affected signaling via the TCR. Although the early events in the signaling cascade, such as the phosphorylation of ZAP70 was intact, downstream activation of ERK was reduced. Endogenous VIP has a very short lifespan and therefore localized production is likely to impact naïve T cell activation. To map the cellular sources of VIP we generated strains of VIP-lineagetracing mice. Preliminary analysis shows strong expression in multiple neurons. These data suggest that VIP secreted by neurons has the potential to influence T cell response in a broad manner at the early stage of an immune response.