Superior Cervical Ganglia Neurons Induce Foxp3+Regulatory T Cells via Calcitonin Gene-Related Peptide

The nervous and immune systems communicate bidirectionally, utilizing diverse molecular signals including cytokines and neurotransmitters to provide an integrated response to changes in the body's internal and external environment. Although, neuro-immune interactions are becoming better understood under inflammatory circumstances and it has been evidenced that interaction between neurons and T cells results in the conversion of encephalitogenic T cells to T regulatory cells, relatively little is known about the communication between neurons and naive T cells. Here, we demonstrate that following co-culture of naive CD4(+) T cells with superior cervical ganglion neurons, the percentage of Foxp3 expressing CD4(+) CD25(+) cells significantly increased. This was mediated in part by immune-regulatory cytokines TGF-beta and IL-10, as well as the neuropeptide calcitonin gene-related peptide while vasoactive intestinal peptide was shown to play no role in generation of T regulatory cells. Additionally, T cells co-cultured with neurons showed a decrease in the levels of proinflammatory cytokine IFN-gamma released upon in vitro stimulation. These findings suggest that the generation of Tregs may be promoted by naive CD4(+) T cell: neuron interaction through the release of neuropeptide CGRP.