Publicação
Modulation of invariant natural killer T (INKT)-Cell function in immune-mediated diseases
| Resumo: | Invariant natural killer T (iNKT) cells are innate-like lymphocytes that respond to glycolipids with rapid cytokine release, including IFN-Ү, IL-4 or IL-17, thus recapitulating many features of T-helper (Th) responses. Furthermore, the host laboratory recently showed that iNKT cells can induce de novo expression of Foxp3 in presence of TGF-β, thereby adopting a regulatory phenotype similar to Treg cells. Specific Th-like cytokine patterns have been associated to distinct iNKT-cell NK1.1/CD4 subsets. We investigated the plasticity of these four subpopulations in response to the same stimuli driving the polarization of conventional CD4 T cells towards a Treg, “Th9” or Th17-like phenotype in vitro. Polarization was achieved within all iNKT-cell subsets, although with different efficiencies. Importantly, NK1.1/CD4 were down-modulated, suggesting their expression probably define functional states rather than fixed lineages. Using an allergic airways disease model where iNKT cells play a pathogenic role, we showed that anti-CD4 monoclonal antibody (MAb) treatment decreased iNKT-cell infiltrates in the airways and modified iNKT-cell phenotype in the draining lymph nodes, which correlated with disease prevention. Our results also show that, in a model of experimental autoimmune encephalomyelitis where a protective role is attributed to iNKT cells, anti-CD4 MAb treatment, as well as α-GalCer (a specific iNKT agonist) administration can prevent the disease. This correlated with increased iNKT-cell content in cervical LNs and spleen compared to sick mice and, more importantly, with higher numbers of Foxp3+ iNKT cells. Collectively, our results reveal that all NK1.1/CD4 iNKT-cell subsets share a similar plasticity in response to environmental stimuli, thus challenging the general assumption that cytokine expression is restricted to certain iNKT subpopulations. Finally, we also show that iNKT cells can be subject to immunomodulation protocols that prevent diseases, which renders this population a new potential target for pharmacological intervention aiming to control immune mediated disorders. |
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| Autores principais: | Almeida, Catarina Filipa dos Santos Sá e |
| Assunto: | Células T "natural killer" invariantes Polarização in vitro TGF-β Asma alérgica Encefomielite autoimune experimental Células T reguladoras Subtipos T helper Tolerância Teses de mestrado - 2009 |
| Ano: | 2009 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Invariant natural killer T (iNKT) cells are innate-like lymphocytes that respond to glycolipids with rapid cytokine release, including IFN-Ү, IL-4 or IL-17, thus recapitulating many features of T-helper (Th) responses. Furthermore, the host laboratory recently showed that iNKT cells can induce de novo expression of Foxp3 in presence of TGF-β, thereby adopting a regulatory phenotype similar to Treg cells. Specific Th-like cytokine patterns have been associated to distinct iNKT-cell NK1.1/CD4 subsets. We investigated the plasticity of these four subpopulations in response to the same stimuli driving the polarization of conventional CD4 T cells towards a Treg, “Th9” or Th17-like phenotype in vitro. Polarization was achieved within all iNKT-cell subsets, although with different efficiencies. Importantly, NK1.1/CD4 were down-modulated, suggesting their expression probably define functional states rather than fixed lineages. Using an allergic airways disease model where iNKT cells play a pathogenic role, we showed that anti-CD4 monoclonal antibody (MAb) treatment decreased iNKT-cell infiltrates in the airways and modified iNKT-cell phenotype in the draining lymph nodes, which correlated with disease prevention. Our results also show that, in a model of experimental autoimmune encephalomyelitis where a protective role is attributed to iNKT cells, anti-CD4 MAb treatment, as well as α-GalCer (a specific iNKT agonist) administration can prevent the disease. This correlated with increased iNKT-cell content in cervical LNs and spleen compared to sick mice and, more importantly, with higher numbers of Foxp3+ iNKT cells. Collectively, our results reveal that all NK1.1/CD4 iNKT-cell subsets share a similar plasticity in response to environmental stimuli, thus challenging the general assumption that cytokine expression is restricted to certain iNKT subpopulations. Finally, we also show that iNKT cells can be subject to immunomodulation protocols that prevent diseases, which renders this population a new potential target for pharmacological intervention aiming to control immune mediated disorders. |
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