The effect of APRIL on the migration of thymocytes / O efeito de APRIL na migração de timócitos

AUTOR(ES)
DATA DE PUBLICAÇÃO

2009

RESUMO

Proteins of the tumor necrosis factor (TNF) family play an important role in many biological processes like cell proliferation, differentiation, survival and death. APRIL (A Proliferation-Inducing Ligand) is a member of this cytokine family, promotes tumor proliferation and survival, and modulates B cells activities, enhancing cell survival and antibody production. However, whether APRIL exerts any effect on T cells remains unclear. APRIL acts by interacting with two receptors, BCMA and TACI, both expressed on lymphocytes. Additionally, APRIL binds to cell surface heparan sulphate proteoglycans (HSPG). Transgenic mice overexpressing APRIL develop a B-1 cell neoplasia. In preliminary analysis, we observed by immunohistochemistry, an increase in B220+ cells in the thymus from APRIL Transgenic mice compared to the controls. The thymus is a central lymphoid organ in which T cell differentiation occurs. This process is deeply dependent on thymocyte migration throughout organ, and for that the thymocytes interact with the thymic epithelial cells (TEC) and extracellular matrix molecules such as fibronectin and laminin. APRIL effects in the thymus remain unknown. This work aimed to study the effect of APRIL on thymocyte migration of normal mice. Firstly, we investigated whether APRIL could modulate thymocyte survival and proliferation. We did not find any alterations in response to in vitro treatment with APRIL recombinant protein. Even though, the ex vivo migration assays revealed a chemorrepulsive effect probably owning to a decrease on thymocyte adhesion as showed by co-culture with TEC. Interestingly, these results did not correlate with any difference in the membrane expression of fibronectin or laminin receptors (respectively VLA-4 / VLA-5, and VLA-6) on thymocyte subpopulations. APRIL chemorrepulsive effect was enhanced by CXCL12 and laminin (but not by fibronectin). Besides, differing from TEC, thymocytes did not express APRIL receptors. Nevertheless, pre-treatment with heparin partially blocks migration, suggesting that the effect of APRIL on thymocyte migration is mediated by HSPG interaction. In conclusion, APRIL seems to stimulate thymocyte migration, and downregulates cell adhesion, by interacting with HSPG.

ASSUNTO(S)

camundongos transgênicos/anormalidades receptores do fator de necrose tumoral fatores de necrose tumoral/imunologia mice, transgenic/abnormalities receptors, tumor necrosis factor tumor necrosis factors/immunology imunologia

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