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Projeto de investigação
Center for Interdisciplinary Research in Animal Health
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Ageing affects the CD4+ T cell polarization and mucosal tropism induced by TLR2/TLR4-activated dendritic cells
Publication . Zúquete, Sara; Ferreira, Mariana; Delgado, Inês L.S.; Rosa, Maria Teresa; Mendes, Ana Catarina; Santos, Dulce; Nolasco, Sofia; Graca, Luis; Leitão, Alexandre; Basto, Afonso P.; Faculdade de Ciências e Tecnologia (FCT); Oxford University Press
Toll-like receptor (TLR)2 activation induces aldehyde dehydrogenase enzymes in nonmucosal dendritic cells (DCs) enabling them to metabolize vitamin A into all-trans retinoic acid, which induces the expression of mucosal homing molecules (α4β7 and CCR9) in the activated T cells. Recently, we have shown that the simultaneous activation of nonmucosal DCs through TLR2 and TLR4 maintains such capacity while reinforcing the polarization of primed CD4+ T cells towards Th1. Here, we observed that TLR2/TLR4 stimulation of aged DCs leads to the production of less TNFα and more IL-10 and that CD4+ T cells primed by those DCs express lower levels of the mucosal homing receptor CCR9 and produce less type-1 (IFNγ) and more type-2 (IL-4 and IL-13) cytokines. These results emphasize the importance of considering the age-related alterations in DC function when developing novel immunomodulation strategies that rely on the DC-T cell crosstalk through stimulation of pattern recognition receptors.
Combined TLR2/TLR4 activation equip non-mucosal dendritic cells to prime Th1 cells with gut tropism
Publication . Zúquete, Sara; Ferreira, Mariana; Delgado, Inês L.S.; Gazalle, Paula; Andaluz, Stephanie; Rosa, Maria Teresa; Mendes, Ana Catarina; Santos, Dulce; Nolasco, Sofia; Graça, Luís; Leitão, Alexandre; Basto, Afonso P.; Faculdade de Ciências e Tecnologia (FCT); Elsevier
Activated CD4+ T cells located at mucosal surfaces orchestrate local effector immune mechanisms. When properly polarized, these cells contribute to block infections at early stages and may be essential to restrain the local growth of mucosal tumors, playing a critical role in host protection. How CD4+ T cells simultaneously integrate gut-homing instructions and Th polarization signals transmitted by TLR activated dendritic cells (DCs) is unknown. Here, we show that the combined activation through TLR2, which alone does not induce a clear Th polarization, and TLR4, which alone does not imprint mucosal tropism, equip non-mucosal DCs to prime gut-homing CD4+ T cells with reinforced Th1 polarization. These results show that targeting DCs with combined innate stimuli with distinct properties is a rational strategy to program the outcome of T cell polarization and simultaneously control their tissue tropism. Exploring this strategy could enhance the efficacy of vaccines and immune cell therapies.
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Entidade financiadora
Fundação para a Ciência e a Tecnologia
Programa de financiamento
6817 - DCRRNI ID
Número da atribuição
UID/CVT/00276/2019