RESUMEN
T cells are imprinted to express tissue-specific homing receptors upon activation in tissue-draining lymph nodes, resulting in their migration to the site of Ag entry. Expression of gut-homing molecules alpha(4)beta(7) and CCR9 is induced by retinoic acid, a vitamin A metabolite produced by retinal dehydrogenases, which are specifically expressed in dendritic cells as well as stromal cells in mucosa-draining lymph nodes. In this study, we demonstrate that mesenteric lymph node stromal cell-derived retinoic acid can directly induce the expression of gut-homing molecules on proliferating T cells, a process strongly enhanced by bone marrow-derived dendritic cells in vitro. Therefore, cooperation of sessile lymph node stromal cells with mobile dendritic cells warrants the imprinting of tissue specific homing receptors on activated T cells.
Asunto(s)
Células Dendríticas/inmunología , Integrinas/inmunología , Intestinos/inmunología , Ganglios Linfáticos/inmunología , Linfocitos T/inmunología , Aldehído Deshidrogenasa/inmunología , Aldehído Deshidrogenasa/metabolismo , Animales , Células Dendríticas/enzimología , Células Dendríticas/metabolismo , Trasplante de Células Madre Hematopoyéticas , Integrinas/metabolismo , Ganglios Linfáticos/enzimología , Ganglios Linfáticos/metabolismo , Ratones , Ratones Congénicos , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Receptores CCR/inmunología , Receptores CCR/metabolismo , Células del Estroma/citología , Células del Estroma/inmunología , Células del Estroma/metabolismo , Linfocitos T/metabolismoRESUMEN
The amino acid tryptophan is essential for the proliferation and survival of cells. Modulation of tryptophan metabolism has been described as an important regulatory mechanism for the control of immune responses. The enzyme IDO degrades the indole moiety of tryptophan, not only depleting tryptophan but also producing immunomodulatory metabolites called kynurenines, which have apoptosis-inducing capabilities. In this study, we show that IDO is more highly expressed in nonplasmacytoid dendritic cells of the nose draining lymph nodes (LNs), which form a unique environment to induce tolerance to inhaled Ags, when compared with other peripheral LNs. Upon blockade of IDO during intranasal OVA administration, Ag-specific immune tolerance was abrogated. Analysis of Ag-specific T cells in the LNs revealed that inhibition of IDO resulted in enhanced survival at 48 h after antigenic stimulation, although this result was not mediated through alterations in apoptosis or cell proliferation. Furthermore, no differences were found in CD4(+) T cells expressing FoxP3. Our data suggest that the level of IDO expression in dendritic cells, present in nose draining LNs, allows for the generation of a sufficient number of regulatory T cells to control and balance effector T cells in such a way that immune tolerance is induced, whereas upon IDO blockade, effector T cells will outnumber regulatory T cells, leading to immunity.
Asunto(s)
Administración Intranasal , Células Dendríticas/enzimología , Tolerancia Inmunológica/fisiología , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Mucosa Nasal/inmunología , Traslado Adoptivo , Animales , Femenino , Factores de Transcripción Forkhead/biosíntesis , Indolamina-Pirrol 2,3,-Dioxigenasa/inmunología , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/administración & dosificación , Ovalbúmina/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
The notion that the mucosal immune system maintains a tolerogenic response to harmless Ags while continually being challenged with microbial products seems an enigma. The aim of this study was to unravel mechanisms that are involved in regulating the development of tolerance under constant microbial pressure. The tolerogenic response to Ags administered via the nasal mucosa is dependent on the organized lymphoid tissue of the cervical lymph nodes (LN). We show that cervical LN differentially express secretory leukoprotease inhibitor (SLPI) compared with peripheral LN. SLPI was expressed by dendritic cells (DCs) and because SLPI is known to suppress LPS responsiveness, it was hypothesized that its expression in mucosal DCs may be required to regulate cellular activation to microbial products. Indeed, compared with wild-type controls, bone marrow-derived DCs from SLPI(-/-) mice released more inflammatory cytokines and enhanced T cell proliferation after stimulation with low dose LPS. This increased sensitivity to LPS was accompanied by increased NF-kappaB p65 activation in SLPI(-/-) DCs. In vivo, nasal application of OVA with LPS to SLPI(-/-) mice resulted in enhanced DC activation in the cervical LN reflected by increased costimulatory molecule expression and release of inflammatory cytokines. This led to failure to maintain tolerance to nasal OVA application in the presence of low doses of LPS. We propose that expression of SLPI functions as a rheostat by controlling the level of bacterial stimuli that induce mucosal DC activation. As such, it regulates the quality of the ensuing Ag-specific immune response in the mucosa draining LN.