Publicação
Sensing and transcriptional requirements of innate lymphoid cells
| Nome: | Descrição: | Tamanho: | Formato: | |
|---|---|---|---|---|
| 22.65 MB | Adobe PDF |
Autores
Resumo(s)
Innate lymphoid cells (ILCs) are a novel family of effector immune cells that have critical roles in tissue homeostasis. They localize at mucosal surfaces and can be divided into two subgroups: the cytotoxic and the helper-like ILCs (helper-ILCs). The cytotoxic-ILC arm, is composed by NK cells which have critical roles in viral and tumor immunity. Helper-like ILCs, which roles mirror T helper cell functions, fall within three main subsets (ILC1, ILC2 and ILC3). ILC3s also comprises fetal Lymphoid Tissue inducer (LTi) cells that during embryonic development shape the formation of secondary lymphoid organs, such as Peyer’s Patches (PP) and lymph nodes (LN). Despite distinct transcriptional requirements for differentiation, ILCs arise from the same common lymphoid progenitor that gives rise to adaptive T and B lymphocytes. The work in this thesis starts by interrogating the role of the transcription factor Nuclear factor, interleukin 3 regulated (NFIL3), in helper-ILCs development. NFIL3 is known to regulate NK cell development and it can also integrate circadian cues. We found that NFIL3 is crucial for helper-ILCs development. Our results demonstrate that in the absence of Nfil3, fetal and adult ILC homeostasis is severely compromised. Consequently, PP fail to form and LN size is reduced. All adult ILC lineages are also consistently decreased at mucosal sites. Furthermore, conditional deletion of Nfil3 lead us to conclude that this gene acts in a cell-intrinsic manner and before commitment to defined ILC lineages. Interleukin 7 (IL-7) induced Nfil3 expression, suggesting that local environmental cues may regulate this process. Interestingly, we further demonstrated that NFIL3 binds to the promotor of Id2, the master transcription factor for all helper-ILCs, in the common helper innate lymphoid progenitor (CHILP), thus indicating that NFIL3 critically regulates CHILP progenitors as they emerge from the common lymphoid progenitor. It is well established that ILC subsets integrate host-derived cytokine and alarmin cues. In addition, ILCs can also respond to microbial cues, dietary metabolites, and neuronal signals. As such we interrogated whether circadian cues could regulate ILC function. We found that the transcription factor of the molecular clock machinery, Bmal1, is critical to ILC3 function and homeostasis. ILC3s expressed the circadian clock machinery, and presented circadian oscillatory patterns. In agreement, absence of BMAL1 lead to a cell-intrinsic impairment of mucosal ILC3 homeostasis. We found a decrease in CCR9, and α4β7 expression, suggesting that the ability of homing to the intestine is affected. The reduced number of ILC3s in the gut lead to an increased susceptibility in response to Citrobacter rodentium infection. Strikingly, ILC3s were regulated by brain-derived light cues, establishing the environmental link between circadian environmental factors, brain activity, and mucosal immunity. Altogether, this thesis sheds light into the mechanistic regulation of ILC development, unraveling novel functions of circadian brain-derived light cues in mucosal immunity.
Descrição
Tese de doutoramento, Ciências Biomédicas (Imunologia), Universidade de Lisboa, Faculdade de Medicina, 2018
Palavras-chave
ILC Desenvolvimento NFIL3 Circadiano Teses de doutoramento - 2018