RESUMO
Viral clearance requires effector T-cell egress from the draining lymph node (dLN). The mechanisms that regulate the complex process of effector T-cell egress from the dLN after infection are poorly understood. Here, we visualized endogenous pathogen-specific effector T-cell migration within, and from, the dLN. We used an inducible mouse model with a temporally disrupted sphingosine-1-phosphate receptor-1 (S1PR1) gene specifically in endogenous effector T cells. Early after infection, WT and S1PR1(-/-) effector T cells localized exclusively within the paracortex. This localization in the paracortex by CD8 T cells was followed by intranodal migration by both WT and S1PR1(-/-) T cells to positions adjacent to both cortical and medullary lymphatic sinuses where the T cells exhibited intense probing behavior. However, in contrast to WT, S1PR1(-/-) effector T cells failed to enter the sinuses. We demonstrate that, even when LN retention signals such as CC chemokine receptor 7 (CCR7) are down-regulated, T cell intrinsic S1PR1 is the master regulator of effector T-cell emigration from the dLN.
Assuntos
Infecções/imunologia , Infecções/patologia , Linfonodos/imunologia , Linfonodos/patologia , Receptores de Lisoesfingolipídeo/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia , Animais , Movimento Celular/imunologia , Células Endoteliais/imunologia , Células Endoteliais/patologia , Ativação Linfocitária , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores de Lisoesfingolipídeo/deficiência , Receptores de Lisoesfingolipídeo/genética , Receptores de Esfingosina-1-Fosfato , Estomatite Vesicular/imunologia , Estomatite Vesicular/patologia , Vírus da Estomatite Vesicular IndianaRESUMO
Tissue-resident macrophages are a diverse population of cells that perform specialized functions including sustaining tissue homeostasis and tissue surveillance. Here, we report an interstitial subset of CD169+ lung-resident macrophages that are transcriptionally and developmentally distinct from alveolar macrophages (AMs). They are primarily localized around the airways and are found in close proximity to the sympathetic nerves in the bronchovascular bundle. These nerve- and airway-associated macrophages (NAMs) are tissue resident, yolk sac derived, self-renewing, and do not require CCR2+ monocytes for development or maintenance. Unlike AMs, the development of NAMs requires CSF1 but not GM-CSF. Bulk population and single-cell transcriptome analysis indicated that NAMs are distinct from other lung-resident macrophage subsets and highly express immunoregulatory genes under steady-state and inflammatory conditions. NAMs proliferated robustly after influenza infection and activation with the TLR3 ligand poly(I:C), and in their absence, the inflammatory response was augmented, resulting in excessive production of inflammatory cytokines and innate immune cell infiltration. Overall, our study provides insights into a distinct subset of airway-associated pulmonary macrophages that function to maintain immune and tissue homeostasis.
Assuntos
Macrófagos Alveolares/imunologia , Neurônios/imunologia , Animais , Homeostase/imunologia , Fator Estimulador de Colônias de Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Saco Vitelino/citologia , Saco Vitelino/imunologiaRESUMO
Influenza A virus belongs to the family of Orthomyxoviridae. It is an enveloped virus with a negative sense RNA segmented genome that encodes for 11 viral genes. This virus has evolved a number of mechanisms that enable it to invade host cells and subvert the host cell machinery for its own purpose, that is, for the sole production of more virus. Two of the mechanisms that the virus uses are "cap-snatching" and preventing the host cell from expressing its own genes. This mini-review provides a brief overview as to how the virus is able to invade host cells, replicate itself, and exit the host cell.
Assuntos
Vírus da Influenza A/fisiologia , Interações Hospedeiro-Patógeno , Humanos , Vírus da Influenza A/genética , Influenza Humana/virologia , Ribonucleoproteínas/metabolismo , Montagem de Vírus , Internalização do VírusRESUMO
Memory CD8+ T cells were originally thought to exist as two populations (effector and central memory). In recent years, a third population called resident memory T cells has been discovered and further to this these populations are being divided into different subtypes. Understanding the function and developmental pathways of memory CD8+ T cells is key to developing effective therapies against cancer and infectious diseases. Here we have reviewed what is currently known about all three subsets of memory CD8+ T populations and as to how each population was originally discovered and the developmental pathways of each subpopulation. Each memory population appears to play a distinct role in adaptive immune responses but we are still a long way from understanding how the populations are generated and what roles they play in protection against invading pathogens and if they contribute to the pathogenesis of inflammatory diseases.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Imunoterapia Adotiva/métodos , Infecções/terapia , Neoplasias/terapia , Subpopulações de Linfócitos T/imunologia , Imunidade Adaptativa , Animais , Linfócitos T CD8-Positivos/transplante , Interações Hospedeiro-Patógeno , Humanos , Infecções/imunologia , Neoplasias/imunologia , Subpopulações de Linfócitos T/transplanteRESUMO
The spleen is an important site for generating protective immune responses against pathogens. After infection, immune cells undergo rapid reorganization to initiate and maintain localized inflammatory responses; however, the mechanisms governing this spatial and temporal cellular reorganization remain unclear. We show that the strategic position of splenic marginal zone CD169+ macrophages is vital for rapid initiation of antibacterial responses. In addition to controlling initial bacterial growth, CD169+ macrophages orchestrate a second phase of innate protection by mediating the transport of bacteria to splenic T cell zones. This compartmentalization of bacteria within the spleen was essential for driving the reorganization of innate immune cells into hierarchical clusters and for local interferon-γ production near sites of bacterial replication foci. Our results show that both phases of the antimicrobial innate immune response were dependent on CD169+ macrophages, and, in their absence, the series of events needed for pathogen clearance and subsequent survival of the host was disrupted. Our study provides insight into how lymphoid organ structure and function are related at a fundamental level.
Assuntos
Imunidade Inata , Listeria monocytogenes/imunologia , Listeriose/imunologia , Macrófagos/imunologia , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Baço/imunologia , Baço/microbiologia , Animais , Humanos , Interferon gama/imunologia , Listeria monocytogenes/fisiologia , Listeriose/microbiologia , Macrófagos/microbiologia , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Baço/anatomia & histologia , Baço/citologia , Linfócitos T/imunologiaAssuntos
Proteínas de Drosophila/genética , Células Germinativas/metabolismo , RNA Interferente Pequeno/genética , Complexo de Inativação Induzido por RNA/genética , Células-Tronco/metabolismo , Animais , Proteínas Argonautas , Proliferação de Células , Proteínas de Drosophila/metabolismo , Feminino , Células Germinativas/citologia , Masculino , Fatores de Iniciação de Peptídeos/genética , Fatores de Iniciação de Peptídeos/metabolismo , RNA Interferente Pequeno/metabolismo , Complexo de Inativação Induzido por RNA/metabolismo , Células-Tronco/citologiaRESUMO
Since the discovery that conjugation of ubiquitin to proteins can drive proteolytic degradation, ubiquitination has been shown to perform a diverse range of functions in the cell. It plays an important role in endocytosis, signal transduction, trafficking of vesicles inside the cell, and even DNA repair. The process of ubiquitination-mediated control has turned out to be remarkably complex, involving a diverse array of proteins and many levels of control. This review focuses on a family of structurally related E3 ligases termed the membrane-associated RING-CH (MARCH) ubiquitin ligases, which were originally discovered as structural homologs to the virals E3s, K3, and K5 from Kaposi's sarcoma-associated herpesvirus (KSHV). These proteins contain a catalytic RING-CH finger and are typically membrane-bound, with some having up to 14 putative transmembrane domains. Despite several lines of evidence showing that the MARCH proteins play a complex and essential role in several cellular processes, this family remains understudied.
RESUMO
Like their host cells, many viruses produce noncoding (nc)RNAs. These show diversity with respect to time of expression during viral infection, length and structure, protein-binding partners and relative abundance compared with their host-cell counterparts. Viruses, with their limited genomic capacity, presumably evolve or acquire ncRNAs only if they selectively enhance the viral life cycle or assist the virus in combating the host's response to infection. Despite much effort, identifying the functions of viral ncRNAs has been extremely challenging. Recent technical advances and enhanced understanding of host-cell ncRNAs promise accelerated insights into the RNA warfare mounted by this fascinating class of RNPs.