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Radical reversal of vasoactive intestinal peptide (VIP) receptors during early lymphopoiesis

Author:
Vomhof-DeKrey, Emilie E., Sandy, Ashley R., Failing, Jarrett J., Hermann, Rebecca J., Hoselton, Scott A., Schuh, Jane M., Weldon, Abby J., Payne, Kimberly J., Dorsam, Glenn P.
Source:
Peptides 2011 v.32 no.10 pp. 2058-2066
ISSN:
0196-9781
Subject:
T-lymphocytes, chemotaxis, cytokines, gene expression, messenger RNA, mice, thymocytes, thymus gland, transcription factors, vasoactive intestinal peptide, vasoactive intestinal peptide receptors
Abstract:
Successful thymocyte maturation is essential for normal, peripheral T cell function. Vasoactive intestinal peptide (VIP) is a neuropeptide which is highly expressed in the thymus that has been shown to modulate thymocyte development. VIP predominantly binds two G protein coupled receptors, termed vasoactive intestinal peptide receptor 1 (VPAC1) and VPAC2, but their expression profiles in CD4⁻/CD8⁻ (double negative, DN) thymocyte subsets, termed DN1–4, have yet to be identified. We hypothesized that a high VPAC1:VPAC2 ratio in the earliest thymocyte progenitors (ETP cells) would be reversed during early lymphopoiesis as observed in activated, peripheral Th₂ cells, as the thymus is rich in Th₂ cytokines. In support of this hypothesis, high VPAC1 mRNA levels decreased 1000-fold, accompanied with a simultaneous increase in VPAC2 mRNA expression during early thymocyte progenitor (ETP/DN1)→DN3 differentiation. Moreover, arrested DN3 cells derived from an Ikaros null mouse (JE-131 cells) failed to completely reverse the VIP receptor ratio compared to wild type DN3 thymocytes. Surprisingly, VPAC2⁻/⁻ mice did not show significant changes in relative thymocyte subset numbers. These data support the notion that both VPAC1 and VPAC2 receptors are dynamically regulated by Ikaros, a master transcriptional regulator for thymocyte differentiation, during early thymic development. Moreover, high VPAC1 mRNA is a novel marker for the ETP population making it enticing to speculate that the chemotactic VIP/VPAC1 signaling axis may play a role in thymocyte movement. Also, despite the results that VPAC2 deficiency did not affect thymic subset numbers, future studies are necessary to determine whether downstream T cell phenotypic changes manifest themselves, such as a propensity for a Th₁ versus Th₂ polarization.
Agid:
1054266