Neuromuscular regulation of T-cell activation

Recent investigations in our laboratory have shown that murine intestinal smooth muscle cells (ISMCs) can exert an immunomodulatory effect on T-cells. Therefore, we examined the effects of substance P, calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) on the ability of ISMCs to modulate T-cell proliferation and lymphokine generation. T-cell proliferation was observed when these cells were co-cultured with IFN-pretreated C57/BL6 ISMCs which expressed major histocompatibility complex II (MHC II), but not during T-cell co-culture with C2D (MHC II -/-) ISMCs pretreated in the same manner. T-cell proliferation during co-culture with C57/BL6 ISMCs was also associated with significantly enhanced T-cell synthesis of IFN. When CGRP (at 10(-9) M), but not substance P or VIP, was added to C57/BL6 ISMCs during the IFN-pretreatment period. T-cell proliferation was significantly increased. However, increased T-cell proliferation was not observed if the concentration of CGRP was increased to 10(-6) M. At the higher concentration, addition of substance P or VIP during the pretreatment period significantly inhibited the subsequent T-cell proliferation. Pretreatment of C57/BL6 ISMCs with any of the three neuropeptides and IFN resulted in the diminished production of IL-4 and IFN by co-cultured T-cells. A similar pattern of cytokine secretion was observed during T-cell co-culture with IFN- and neuropeptide-pretreated C2D ISMCs except when 10(-6) M substance P was added; IFN secretion by co-cultured T-cells was increased 4-fold under these conditions. Taken together, these data show a direct modulatory role for neuropeptides in the interaction between ISMCs and T-cells and suggest that, in general, neuropeptides may dampen immune responses in the neuromuscular layers of the inflamed intestine.