RESUMO
Through immune memory, infections have a lasting effect on the host. While memory cells enable accelerated and enhanced responses upon rechallenge with the same pathogen, their impact on susceptibility to unrelated diseases is unclear. We identify a subset of memory T helper 1 (Th1) cells termed innate acting memory T (TIA) cells that originate from a viral infection and produce IFN-γ with innate kinetics upon heterologous challenge in vivo. Activation of memory TIA cells is induced in response to IL-12 in combination with IL-18 or IL-33 but is TCR independent. Rapid IFN-γ production by memory TIA cells is protective in subsequent heterologous challenge with the bacterial pathogen Legionella pneumophila. In contrast, antigen-independent reactivation of CD4+ memory TIA cells accelerates disease onset in an autoimmune model of multiple sclerosis. Our findings demonstrate that memory Th1 cells can acquire additional TCR-independent functionality to mount rapid, innate-like responses that modulate susceptibility to heterologous challenges.
Assuntos
Imunidade Inata , Memória Imunológica , Interferon gama , Células Th1 , Células Th1/imunologia , Animais , Memória Imunológica/imunologia , Camundongos , Interferon gama/metabolismo , Interferon gama/imunologia , Células T de Memória/imunologia , Camundongos Endogâmicos C57BL , Legionella pneumophila/imunologia , Esclerose Múltipla/imunologia , Interleucina-12/metabolismo , Interleucina-12/imunologiaRESUMO
Epidemiological data suggest that previous infections can alter an individual's susceptibility to unrelated diseases. Nevertheless, the underlying mechanisms are not completely understood. Substantial research efforts have expanded the classical concept of immune memory to also include long-lasting changes in innate immunity and antigen-independent reactivation of adaptive immunity. Collectively, these processes provide possible explanations on how acute infections might induce long-term changes that also affect immunity to unrelated diseases. Here, we review lasting changes the immune compartment undergoes upon infection and how infection experience alters the responsiveness of immune cells towards universal signals. This heightened state of alert enhances the ability of the immune system to combat even unrelated infections but may also increase susceptibility to autoimmunity. At the same time, infection-induced changes in the regulatory compartment may dampen subsequent immune responses and promote pathogen persistence. The concepts presented here outline how infection-induced changes in the immune system may affect human health.
Assuntos
Suscetibilidade a Doenças/imunologia , Imunidade Inata/imunologia , Memória Imunológica/imunologia , Infecções/imunologia , Animais , Autoimunidade , Reações Cruzadas/imunologia , Citocinas/imunologia , Humanos , Ativação Linfocitária/imunologia , Camundongos , Linfócitos T/imunologiaRESUMO
The eight-subunit COP9 signalosome (CSN) is conserved from filamentous fungi to humans and functions at the interface between cellular signalling and protein half-life control. CSN consists of six PCI and two MPN domain proteins and forms a scaffold for additional interacting proteins. CSN controls protein stability in the ubiquitin-proteasome system where the MPN domain CSN5/CsnE subunit inactivates cullin-RING ligases. The CSN5/CsnE isopeptidase functions as deneddylase and removes the ubiquitin-like protein Nedd8. The six PCI domain proteins of human CSN form a horseshoe-like ring and all eight subunits are connected by a bundle of C-terminal α-helices. We show that single deletions of any csn subunit of Aspergillus nidulans resulted in the lack of deneddylase activity and identical defects in the coordination of development and secondary metabolism. The CSN1/CsnA N-terminus is dispensable for deneddylase activity but required for asexual spore formation. Complex analyses in mutant strains revealed the presence of a seven-subunit pre-CSN without catalytic activity. Reconstitution experiments with crude extracts of deletion strains and recombinant proteins allowed the integration of CSN5/CsnE into pre-CSN resulting in an active deneddylase. This supports a stable seven subunit pre-CSN intermediate where deneddylase activation in vivo can be controlled by CSN5/CsnE integration as final assembly step.
Assuntos
Aspergillus nidulans/enzimologia , Domínio Catalítico , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Complexos Multiproteicos/química , Complexos Multiproteicos/metabolismo , Peptídeo Hidrolases/química , Peptídeo Hidrolases/metabolismo , Aspergillus nidulans/genética , Aspergillus nidulans/metabolismo , Complexo do Signalossomo COP9 , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Dados de Sequência Molecular , Complexos Multiproteicos/genética , Peptídeo Hidrolases/genética , Ligação Proteica , Estrutura Terciária de Proteína , Subunidades Proteicas/metabolismo , Esporos Fúngicos/metabolismoRESUMO
Regulatory T cells (Tregs) maintain peripheral self-tolerance and limit immune mediated pathology. Like effector T cells, Tregs can specialize in TH1-dominated immune responses and co-express T-bet together with Foxp3. This allows for expression of CXCR3 and efficient homing to sites of TH1 responses. However, whether such functional specialization is paralleled by memory generation among Tregs is unknown. In this study, we investigated the ability of polyclonal Tregs to form functional memory in response to viral infection. Using adoptive transfer models to compare infection-experienced Tregs generated upon acute Lymphocytic Choriomeningitis Virus (LCMV) WE and Vaccinia Virus (VV) infections with naive Tregs, we observed no differences in their phenotype or their in vivo maintenance. When comparing functional properties of infection-experienced and naive Tregs, we found no differences in in vitro suppressive capacity nor in their ability to limit the effector response upon homologous, systemic or local re-challenge in vivo. Our results suggest that no functional Treg memory is generated in the context of systemic LCMV or VV infection, but we cannot rule out the possibility that the generation of Treg memory may be possible in other contexts.
Assuntos
Infecções por Arenaviridae/imunologia , Memória Imunológica , Linfócitos T Reguladores/imunologia , Vacínia/imunologia , Transferência Adotiva , Animais , Infecções por Arenaviridae/virologia , Modelos Animais de Doenças , Humanos , Vírus da Coriomeningite Linfocítica , Camundongos , Linfócitos T Reguladores/transplante , Vacínia/virologia , Vaccinia virus/imunologiaRESUMO
Co-inhibitory pathways have a fundamental function in regulating T cell responses and control the balance between promoting efficient effector functions and restricting immune pathology. The TIGIT pathway has been implicated in promoting T cell dysfunction in chronic viral infection. Importantly, TIGIT signaling is functionally linked to IL-10 expression, which has an effect on both virus control and maintenance of tissue homeostasis. However, whether TIGIT has a function in viral persistence or limiting tissue pathology is unclear. Here we report that TIGIT modulation effectively alters the phenotype and cytokine profile of T cells during influenza and chronic LCMV infection, but does not affect virus control in vivo. Instead, TIGIT has an important effect in limiting immune pathology in peripheral organs by inducing IL-10. Our data therefore identify a function of TIGIT in limiting immune pathology that is independent of viral clearance.
Assuntos
Receptores Imunológicos/metabolismo , Viroses/imunologia , Viroses/patologia , Doença Aguda , Animais , Linfócitos T CD8-Positivos/imunologia , Doença Crônica , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-10/biossíntese , Fígado/patologia , Fígado/virologia , Pulmão/irrigação sanguínea , Pulmão/patologia , Vírus da Coriomeningite Linfocítica/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/patologia , Baço/imunologiaRESUMO
Foxp3+ regulatory T (Treg) cells are essential for maintaining peripheral tolerance and preventing autoimmunity. While genetic factors may predispose for autoimmunity, additional environmental triggers, such as viral infections, are usually required to initiate the onset of disease. Here, we show that viral infection with LCMV results in type I IFN-dependent Treg cell loss that is rapidly compensated by the conversion and expansion of Vß5+ conventional T cells into iTreg cells. Using Vß5-deficient mice, we show that these Vß5+ iTreg cells are dispensable for limiting anti-viral immunity. Rather, the delayed replenishment of Treg cells in Vß5-deficient mice compromises suppression of microbiota-dependent activation of CD8+ T cells, resulting in colitis. Importantly, recovery from clinical symptoms in IBD patients is marked by expansion of the corresponding Vß2+ Treg population in humans. Collectively, we provide a link between a viral trigger and an impaired Treg cell compartment resulting in the initiation of immune pathology.
Assuntos
Infecções por Arenaviridae/imunologia , Autoimunidade , Linfócitos T CD8-Positivos/imunologia , Colite/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Linfócitos T Reguladores/imunologia , Animais , Infecções por Arenaviridae/complicações , Linhagem Celular , Colite/microbiologia , Colo/imunologia , Colo/microbiologia , Fatores de Transcrição Forkhead/metabolismo , Microbioma Gastrointestinal/imunologia , Voluntários Saudáveis , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Ativação Linfocitária/genética , Masculino , Camundongos , Camundongos Knockout , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Linfócitos T Reguladores/metabolismoRESUMO
CD4+Foxp3+ Treg cells are essential for maintaining self-tolerance and preventing excessive immune responses. In the context of Th1 immune responses, co-expression of the Th1 transcription factor T-bet with Foxp3 is essential for Treg cells to control Th1 responses. T-bet-dependent expression of CXCR3 directs Treg cells to the site of inflammation. However, the suppressive mediators enabling effective control of Th1 responses at this site are unknown. In this study, we determined the signature of CXCR3+ Treg cells arising in Th1 settings and defined universal features of Treg cells in this context using multiple Th1-dominated infection models. Our analysis defined a set of Th1-specific co-inhibitory receptors and cytotoxic molecules that are specifically expressed in Treg cells during Th1 immune responses in mice and humans. Among these, we identified the novel co-inhibitory receptor CD85k as a functional predictor for Treg-mediated suppression specifically of Th1 responses, which could be explored therapeutically for selective immune suppression in autoimmunity.
RESUMO
Foxp3+ regulatory T cells (Tregs) maintain immune tolerance, prevent autoimmunity and modulate immune responses during infection and cancer. Recent studies have revealed considerable heterogeneity and plasticity within the Treg compartment, depending on the immunological context, which may result in Tregs losing their suppressive function in inflammatory environments. We review how dysfunctional Tregs contribute to disease pathogenesis in inflammatory conditions and how inappropriate regulatory responses may hamper protective immunity in the context of infection and cancer. We also discuss how Tregs might be targeted therapeutically to re-establish a proper balance between regulatory and effector responses in autoimmunity, infections, and cancer.
Assuntos
Linfócitos T Reguladores , Animais , Autoimunidade , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/farmacologia , Fatores de Transcrição Forkhead/fisiologia , Humanos , Tolerância Imunológica/imunologia , Interleucina-2/farmacologia , Camundongos , Esclerose Múltipla/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/fisiologiaRESUMO
TRIM21 ('tripartite motif-containing protein 21', Ro52) is a ubiquitously expressed cytosolic Fc receptor, which has a potent role in protective immunity against nonenveloped viruses. TRIM21 mediates intracellular neutralisation of antibody-coated viruses, a process called ADIN (antibody-dependent intracellular neutralisation). Our results reveal a similar mechanism to fight bacterial infections. TRIM21 is recruited to the intracellular pathogen Salmonella enterica in epithelial cells early in infection. TRIM21 does not bind directly to S. enterica, but to antibodies opsonising it. Most importantly, bacterial restriction is dependent on TRIM21 as well as on the opsonisation state of the bacteria. Finally, Salmonella and TRIM21 colocalise with the autophagosomal marker LC3, and intracellular defence is enhanced in starved cells suggesting an involvement of the autophagocytic pathway. Our data extend the protective role of TRIM21 from viruses to bacteria and thereby strengthening the general role of ADIN in cellular immunity.