In the course of our studies, we have shown the presence of calcitonin gene related peptide (CGRP) by immunocytochemistry in cell bodies and nerve fibers of the murine thymus and in a sparse innervation of the spleen. Receptors for CGRP have been characterized within these glands, and their activation by physiological levels of CGRP was found to suppress Con A-stimulated proliferation of thymocytes and splenic T cells as well as antigen-specific T-cell proliferation. This suppression is blocked by the antagonist for CGRP (CGRP 8-37). Within the thymus cultures, the antagonist CGRP (8-37) alone enhanced proliferation of thymocytes during Con A stimulation, most likely by inhibiting the endogenous release of CGRP into the culture medium by resident thymocytes. Some of the CGRP-induced suppression of mitogenic stimulation of thymocytes, but not of splenocytes, was due to apoptosis. The antagonist, CGRP(8-37), did not block apoptosis caused by Con A or CGRP but rather enhanced it. Flow cytometric analysis of CGRP-treated cultures using antibodies to cluster determinates (CD) showed that the majority of thymocytes undergoing apoptosis induced by CGRP were of the CD4/CD8 double-positive type. These data indicate that apoptosis in the thymocytes is mediated by a CGRP receptor not sensitive to the antagonist CGRP(8-37). Because proliferation of thymocytes and splenocytes induced by Con A is blocked by this antagonist and splenocytes are refractory to CGRP induced apoptosis, CGRP appears to mediate at least two separate functions on subpopulations of thymocytes and T cells via two different CGRP receptors within the gland. These effects of a neuropeptide exemplify the phenomenon of differential regional regulation of immunity by the autonomic and neuroendocrine systems.
Calcitonin gene-related peptide has been identified by immunocytochemistry within the thymus of fetal through aged adult mice. Calcitonin gene-related peptide positive nerves are observed from embryonic day 17 throughout the lifespan of the mouse. A sparse cell population positive for CGRP is first observed during the late embryonic period at the corticomedullary boundary and the medulla, and it becomes more densely distributed in this region in the adult. In the thymus of the aged mouse the number of CGRP-positive cells diminishes. Pharmacologic studies demonstrated that fresh thymocytes display a receptor Kd for CGRP of 1.17 +/- 0.06 x 10(-10)M and a Bmax of 12.7 +/- 4.7 fmol/mg protein. Functional studies indicate that CGRP is a potent inhibitor of mitogen and antigen-stimulated proliferation of T cells and that it inhibits IL-2 production in cloned splenic T cells. Recent studies suggest that endogenous CGRP may serve as a natural inhibitor of inappropriate induction of mature, antigen-sensitive cells in the thymus as well as play a role in thymocyte education. These findings are discussed in terms of the distribution of CGRP cells and nerve terminals within the thymus and their relationship to positive and negative selection of the T-cell repertoire.
Dehydroepiandrosterone (DHEA) and calcitonin gene-related peptide (CGRP) are naturally occurring substances that are reported to have both opposing and complementary effects on immune functions. In the current study, we sought to determine how they might work together to influence the mitogen-stimulated proliferation of thymocytes. In concanavalin A (ConA)-induced thymocyte proliferation assays, CGRP and DHEA each inhibited proliferation. When the CGRP antagonist CGRP-(8-37) was added to Con A-stimulated thymocytes, the proliferative response was significantly greater than the ConA response alone across a range of ConA doses. Moreover, CGRP-(8-37) blocked the inhibitory effect of DHEA. Individually, CGRP-(8-37), CGRP, DHEA, or their combination did not stimulate thymocyte proliferation in the absence of ConA. CGRP affects the proliferation of CD4+ T cells and thus may be a regional endogenous inhibitor of the proliferation of virgin mature T cells while they remain in the thymus. Furthermore, DHEA may act via endogenous CGRP on the thymus CD4+ T cell population.
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