RESUMO
Macrophages and dendritic cells are involved in the immune response to Mycobacterium tuberculosis (Mtb). Such a response, although extensively studied using animal models and cells from human blood, has not been characterized in cells from pulmonary hilar lymph nodes (PHLN). We characterized populations of myeloid APC from PHLN and determined their expression of CCR2, CCR5, CCR7, CD40, CD54, CD80, and CD86 as well as the cytokine/chemokine microenvironment before and after purified protein derivative (PPD) and mannosilated lipoarabinomannan (ManLAM) stimulation. Results show that there are at least three APC populations in PHLN, defined as CD14highHLA-DRlow/-, CD14dimHLA-DRdim, and CD14-HLA-DRhigh/dendritic cells (DC), with the largest number represented by CD14dimHLA-DRdim cells (where dim indicates intermediate levels). CD14-HLA-DRhigh/DC expressed higher levels of costimulatory molecules and lower levels of CCR2 and CCR5, but all cell populations showed similar CCR7 levels. PPD and ManLAM specifically down-regulated CCR2 expression but not that of CCR5 and CCR7, and such down-regulation was observed on all APC populations. Mtb Ag did not affect the expression of costimulatory molecules. PPD but not ManLAM specifically induced MCP-1/CCL2 production, which was likely associated with the induction of IFN-gamma because this cytokine was highly induced by PPD. We characterized, for the first time, different APC from human PHLN and show that Mtb Ag exert fine and specific regulation of molecules closely associated with the immune response to Mtb infection. Because knowledge of this response in secondary lymphoid tissues is still poorly understood in humans, such studies are necessary and important for a better understanding of lymphoid cell microenvironment and migrating capacities and their role in the immunopathogenesis of tuberculosis.
Assuntos
Células Apresentadoras de Antígenos/imunologia , Antígenos de Bactérias/imunologia , Quimiocina CCL2/metabolismo , Pulmão/imunologia , Linfócitos/imunologia , Receptores CCR2/metabolismo , Adulto , Apresentação de Antígeno , Células Apresentadoras de Antígenos/efeitos dos fármacos , Antígenos de Bactérias/farmacologia , Quimiocina CCL2/análise , Quimiocinas/metabolismo , Criança , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Citometria de Fluxo , Humanos , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Linfonodos/imunologia , Linfócitos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Monócitos/imunologia , Receptores CCR2/análise , Receptores de Quimiocinas/metabolismo , Tuberculina/imunologia , Tuberculina/farmacologiaRESUMO
The majority of knowledge about the role of cytokines and chemokines in controlling Mycobacterium tuberculosis infection mainly derives from animal models. In humans, this knowledge is still mainly limited to the blood compartment or accessible lymphoid organs, such as tonsils. Here, we studied cytokine and chemokine production and their modulation by M. tuberculosis antigens in mononuclear cells from human blood, spleen and hilar lung lymph nodes. Results show that the kinetics and magnitude of cytokine and chemokine production varied according to the tissue of cell origin. Mycobacterium tuberculosis antigens enhanced cytokine and chemokine production in blood, but the enhancement was restricted in spleen and hilar lung lymph node cells. We show, for the first time in humans, differences in cytokine and chemokine microenvironments according to lymphoid tissues, and suggest that these differences may affect the way cells respond to M. tuberculosis infection.