Publicação
The role of IL-7 in the homeostasis of human naive and memory CD4+T cell subsets
| Resumo: | The main focus of this work is to study the homeostasis of human naive and memory CD4+ T cell subsets, particularly assessing the role of IL-7 in this process. For this purpose, we assessed the potentially distinct effects of IL-7 in the homeostasis of naive CD4+ T cell subsets defined by CD31 expression. We describe for the first time the preferential proliferation of the CD31+ subset within adult naive CD4+ T cells in response to IL-7 stimulation. Furthermore, we showed that IL-7-induced proliferation sustained or even increased the level of CD31 expression in CD31+ naive CD4+ T cells, although it did not induce CD31 re-expression in the CD31- subset. We also demonstrated that both IL-7- induced proliferation and CD31 maintenance were dependent on the PI3K pathway. Furthermore, we investigated the mechanisms involved in the restoration of T cell homeostasis following haploidentical haematopoietic stem cell transplantation (HSCT), particularly in the maintenance of the CD31+ naive CD4+ T cell pool. Our data suggest that long term immune reconstitution was successfully achieved in a cohort of haploidentical HSCT recipients, likely through a combination of thymus-dependent and - independent mechanisms which gave rise to balanced CD4+ and CD8+ T cell subsets and to a diverse T cell repertoire. Finally, we focused on memory CD4+ T cell homeostasis in order to clarify the impact of the increasing representation of CD45RA+CD27- CD4+ T cells observed during CMV infection. We sought to determine the replicative and functional potential of these highly differentiated cells, as well as the putative involvement of IL-7 in CD45RA re-expression in memory CD4+ T cells. Our results show that CD45RA+CD27- CD4+ T cells do not constitute an exhausted subset, retaining replicative and functional potential. However, these cells display senescence-associated traits independent of telomere length, which are at least partly mediated by the p38 MAPK pathway. Overall, our data reiterates the contribution of IL-7 signalling to naive and memory CD4+ T cell homeostasis, suggesting a role for IL-7 in the maintenance of the CD31+ naive T cell pool throughout adulthood as well as in the induction of CD45RA on memory CD4+ T cells |
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| Autores principais: | Azevedo, Rita I. |
| Assunto: | Homeostasia Interleucina-7 Linfócitos T CD4-positivos Memória Reconstituição imunológica Senescência Teses de doutoramento - 2011 |
| Ano: | 2011 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | The main focus of this work is to study the homeostasis of human naive and memory CD4+ T cell subsets, particularly assessing the role of IL-7 in this process. For this purpose, we assessed the potentially distinct effects of IL-7 in the homeostasis of naive CD4+ T cell subsets defined by CD31 expression. We describe for the first time the preferential proliferation of the CD31+ subset within adult naive CD4+ T cells in response to IL-7 stimulation. Furthermore, we showed that IL-7-induced proliferation sustained or even increased the level of CD31 expression in CD31+ naive CD4+ T cells, although it did not induce CD31 re-expression in the CD31- subset. We also demonstrated that both IL-7- induced proliferation and CD31 maintenance were dependent on the PI3K pathway. Furthermore, we investigated the mechanisms involved in the restoration of T cell homeostasis following haploidentical haematopoietic stem cell transplantation (HSCT), particularly in the maintenance of the CD31+ naive CD4+ T cell pool. Our data suggest that long term immune reconstitution was successfully achieved in a cohort of haploidentical HSCT recipients, likely through a combination of thymus-dependent and - independent mechanisms which gave rise to balanced CD4+ and CD8+ T cell subsets and to a diverse T cell repertoire. Finally, we focused on memory CD4+ T cell homeostasis in order to clarify the impact of the increasing representation of CD45RA+CD27- CD4+ T cells observed during CMV infection. We sought to determine the replicative and functional potential of these highly differentiated cells, as well as the putative involvement of IL-7 in CD45RA re-expression in memory CD4+ T cells. Our results show that CD45RA+CD27- CD4+ T cells do not constitute an exhausted subset, retaining replicative and functional potential. However, these cells display senescence-associated traits independent of telomere length, which are at least partly mediated by the p38 MAPK pathway. Overall, our data reiterates the contribution of IL-7 signalling to naive and memory CD4+ T cell homeostasis, suggesting a role for IL-7 in the maintenance of the CD31+ naive T cell pool throughout adulthood as well as in the induction of CD45RA on memory CD4+ T cells |
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