RESUMO
The expression of TLRs on epithelial cells provides a first line of defense against invading pathogens. We investigated the regulated expression and function of TLR5 and TLR9 on human keratinocytes, because we found by immunohistochemistry that these TLRs are expressed in distinct layers of the epidermis. We found that TGF-alpha, a growth and differentiation factor that is present during wound healing and in psoriasis, increased the expression of both TLR5 and TLR9 on keratinocytes. In addition, TGF-alpha regulated the function of TLR5 and TLR9, because activation with their respective ligands enhanced the production of IL-8 and human beta-defensins. These findings provide evidence that TGF-alpha up-regulates TLR expression and function, augmenting host defense mechanisms at epithelial surfaces.
Assuntos
Queratinócitos/imunologia , Queratinócitos/metabolismo , Glicoproteínas de Membrana/biossíntese , Glicoproteínas de Membrana/fisiologia , Receptores de Superfície Celular/biossíntese , Receptores de Superfície Celular/fisiologia , Fator de Crescimento Transformador alfa/fisiologia , Adjuvantes Imunológicos/fisiologia , Animais , Proteínas de Ligação a DNA/biossíntese , Cultura em Câmaras de Difusão , Células Epidérmicas , Epiderme/imunologia , Epiderme/metabolismo , Humanos , Interleucina-8/biossíntese , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Técnicas de Cultura de Órgãos , RNA Mensageiro/biossíntese , Receptores de Superfície Celular/genética , Proteínas Recombinantes/farmacologia , Receptor 5 Toll-Like , Receptor Toll-Like 9 , Receptores Toll-Like , Regulação para Cima/genética , Regulação para Cima/imunologia , beta-Defensinas/biossínteseRESUMO
The repertoires of CD1- and MHC-restricted T cells are complementary, permitting the immune recognition of both lipid and peptide Ags, respectively. To compare the breadth of the CD1-restricted and MHC-restricted T cell repertoires, we evaluated T cell responses against lipid and peptide Ags of mycobacteria in leprosy, comparing tuberculoid patients, who are able to restrict the pathogen, and lepromatous patients, who have disseminated infection. The striking finding was that in lepromatous leprosy, T cells did not efficiently recognize lipid Ags from the leprosy pathogen, Mycobacterium leprae, or the related species, Mycobacterium tuberculosis, yet were able to efficiently recognize peptide Ags from M. tuberculosis, but not M. leprae. To identify a mechanism for T cell unresponsiveness against mycobacterial lipid Ags in lepromatous patients, we used T cell clones to probe the species specificity of the Ags recognized. We found that the majority of M. leprae-reactive CD1-restricted T cell clones (92%) were cross-reactive for multiple mycobacterial species, whereas the majority of M. leprae-reactive MHC-restricted T cells were species specific (66%), with a limited number of T cell clones cross-reactive (34%) with M. tuberculosis. In comparison with the MHC class II-restricted T cell repertoire, the CD1-restricted T cell repertoire is limited to recognition of cross-reactive Ags, imparting a distinct role in the host response to immunologically related pathogens.
Assuntos
Antígenos CD1/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Mycobacterium leprae/imunologia , Mycobacterium tuberculosis/imunologia , Receptores de Antígenos de Linfócitos T/biossíntese , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Adulto , Idoso , Apresentação de Antígeno , Antígenos CD1/sangue , Antígenos CD1/metabolismo , Linhagem Celular , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/metabolismo , Feminino , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Hanseníase Virchowiana/imunologia , Hanseníase Virchowiana/microbiologia , Lipídeos/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Subpopulações de Linfócitos T/microbiologia , Subpopulações de Linfócitos T/patologia , Células Th2/imunologia , Células Th2/metabolismo , Tuberculose/imunologia , Tuberculose/microbiologiaRESUMO
Bacterial lipopeptides (bLPs) are increasingly used as adjuvants to activate cell-mediated immune responses to foreign Ags. To explore mechanisms whereby bLPs adjuvant T cell responses, we stimulated human PBMCs with bLPs. We found that bLPs stimulate T cells to proliferate and produce IFN-gamma in an accessory cell-dependent manner and in the absence of exogenous protein Ags. The ability of bLPs to stimulate T cell proliferation was Toll-like receptor 2 dependent and required IL-12, interaction with costimulatory molecules, and MHC proteins. Our data suggest that bLPs adjuvant adaptive Th1 responses by enhancing Ag presentation of endogenous peptides.
