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1.
Nat Immunol ; 21(12): 1563-1573, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33106669

RESUMEN

Chronic cytomegalovirus (CMV) infection leads to long-term maintenance of extraordinarily large CMV-specific T cell populations. The magnitude of this so-called 'memory inflation' is thought to mainly depend on antigenic stimulation during the chronic phase of infection. However, by mapping the long-term development of CD8+ T cell families derived from single naive precursors, we find that fate decisions made during the acute phase of murine CMV infection can alter the level of memory inflation by more than 1,000-fold. Counterintuitively, a T cell family's capacity for memory inflation is not determined by its initial expansion. Instead, those rare T cell families that dominate the chronic phase of infection show an early transcriptomic signature akin to that of established T central memory cells. Accordingly, a T cell family's long-term dominance is best predicted by its early content of T central memory precursors, which later serve as a stem-cell-like source for memory inflation.


Asunto(s)
Evolución Clonal/inmunología , Interacciones Huésped-Patógeno/inmunología , Memoria Inmunológica , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Virosis/etiología , Virosis/metabolismo , Enfermedad Aguda , Animales , Biomarcadores , Enfermedad Crónica , Citomegalovirus/inmunología , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Perfilación de la Expresión Génica , Humanos , Inmunofenotipificación , Ratones , Muromegalovirus/inmunología
2.
Nature ; 631(8019): 189-198, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38898278

RESUMEN

The COVID-19 pandemic is an ongoing global health threat, yet our understanding of the dynamics of early cellular responses to this disease remains limited1. Here in our SARS-CoV-2 human challenge study, we used single-cell multi-omics profiling of nasopharyngeal swabs and blood to temporally resolve abortive, transient and sustained infections in seronegative individuals challenged with pre-Alpha SARS-CoV-2. Our analyses revealed rapid changes in cell-type proportions and dozens of highly dynamic cellular response states in epithelial and immune cells associated with specific time points and infection status. We observed that the interferon response in blood preceded the nasopharyngeal response. Moreover, nasopharyngeal immune infiltration occurred early in samples from individuals with only transient infection and later in samples from individuals with sustained infection. High expression of HLA-DQA2 before inoculation was associated with preventing sustained infection. Ciliated cells showed multiple immune responses and were most permissive for viral replication, whereas nasopharyngeal T cells and macrophages were infected non-productively. We resolved 54 T cell states, including acutely activated T cells that clonally expanded while carrying convergent SARS-CoV-2 motifs. Our new computational pipeline Cell2TCR identifies activated antigen-responding T cells based on a gene expression signature and clusters these into clonotype groups and motifs. Overall, our detailed time series data can serve as a Rosetta stone for epithelial and immune cell responses and reveals early dynamic responses associated with protection against infection.


Asunto(s)
COVID-19 , Multiómica , SARS-CoV-2 , Análisis de la Célula Individual , Femenino , Humanos , Masculino , COVID-19/genética , COVID-19/inmunología , COVID-19/patología , COVID-19/virología , Células Epiteliales/inmunología , Perfilación de la Expresión Génica , Interferones/inmunología , Macrófagos/inmunología , Macrófagos/virología , Nasofaringe/virología , Nasofaringe/inmunología , SARS-CoV-2/crecimiento & desarrollo , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , SARS-CoV-2/fisiología , Linfocitos T/citología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/virología , Factores de Tiempo , Replicación Viral
3.
Nat Immunol ; 23(5): 646-647, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35449418

Asunto(s)
Linfocitos T
4.
Nature ; 609(7926): 354-360, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35978192

RESUMEN

CD8+ T cells that respond to chronic viral infections or cancer are characterized by the expression of inhibitory receptors such as programmed cell death protein 1 (PD-1) and by the impaired production of cytokines. This state of restrained functionality-which is referred to as T cell exhaustion1,2-is maintained by precursors of exhausted T (TPEX) cells that express the transcription factor T cell factor 1 (TCF1), self-renew and give rise to TCF1- exhausted effector T cells3-6. Here we show that the long-term proliferative potential, multipotency and repopulation capacity of exhausted T cells during chronic infection are selectively preserved in a small population of transcriptionally distinct CD62L+ TPEX cells. The transcription factor MYB is not only essential for the development of CD62L+ TPEX cells and maintenance of the antiviral CD8+ T cell response, but also induces functional exhaustion and thereby prevents lethal immunopathology. Furthermore, the proliferative burst in response to PD-1 checkpoint inhibition originates exclusively from CD62L+ TPEX cells and depends on MYB. Our findings identify CD62L+ TPEX cells as a stem-like population that is central to the maintenance of long-term antiviral immunity and responsiveness to immunotherapy. Moreover, they show that MYB is a transcriptional orchestrator of two fundamental aspects of exhausted T cell responses: the downregulation of effector function and the long-term preservation of self-renewal capacity.


Asunto(s)
Linfocitos T CD8-positivos , Receptor de Muerte Celular Programada 1 , Proteínas Proto-Oncogénicas c-myb , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Proliferación Celular , Autorrenovación de las Células , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Inmunoterapia , Selectina L/metabolismo , Células Precursoras de Linfocitos T/citología , Células Precursoras de Linfocitos T/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Proteínas Proto-Oncogénicas c-myb/metabolismo , Virus/inmunología
6.
Proc Natl Acad Sci U S A ; 119(9)2022 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-35217611

RESUMEN

Rapid clonal expansion of antigen-specific T cells is a fundamental feature of adaptive immune responses. It enables the outgrowth of an individual T cell into thousands of clonal descendants that diversify into short-lived effectors and long-lived memory cells. Clonal expansion is thought to be programmed upon priming of a single naive T cell and then executed by homogenously fast divisions of all of its descendants. However, the actual speed of cell divisions in such an emerging "T cell family" has never been measured with single-cell resolution. Here, we utilize continuous live-cell imaging in vitro to track the division speed and genealogical connections of all descendants derived from a single naive CD8+ T cell throughout up to ten divisions of activation-induced proliferation. This comprehensive mapping of T cell family trees identifies a short burst phase, in which division speed is homogenously fast and maintained independent of external cytokine availability or continued T cell receptor stimulation. Thereafter, however, division speed diversifies, and model-based computational analysis using a Bayesian inference framework for tree-structured data reveals a segregation into heritably fast- and slow-dividing branches. This diversification of division speed is preceded already during the burst phase by variable expression of the interleukin-2 receptor alpha chain. Later it is accompanied by selective expression of memory marker CD62L in slower dividing branches. Taken together, these data demonstrate that T cell clonal expansion is structured into subsequent burst and diversification phases, the latter of which coincides with specification of memory versus effector fate.


Asunto(s)
Linfocitos T CD8-positivos/citología , Linaje de la Célula , Animales , Antígenos CD/inmunología , Biomarcadores , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , División Celular , Ratones , Ratones Endogámicos C57BL
7.
Gastroenterology ; 164(4): 550-566, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36587707

RESUMEN

BACKGROUND & AIMS: Infection with Helicobacter pylori strongly affects global health by causing chronic gastritis, ulcer disease, and gastric cancer. Although extensive research into the strong immune response against this persistently colonizing bacterium exists, the specific role of CD8+ T cells remains elusive. METHODS: We comprehensively characterize gastric H pylori-specific CD8+ T-cell responses in mice and humans by flow cytometry, RNA-sequencing, immunohistochemistry, and ChipCytometry, applying functional analyses including T-cell depletion, H pylori eradication, and ex vivo restimulation. RESULTS: We define CD8+ T-cell populations bearing a tissue-resident memory (TRM) phenotype, which infiltrate the gastric mucosa shortly after infection and mediate pathogen control by executing antigen-specific effector properties. These induced CD8+ tissue-resident memory T cells (TRM cells) show a skewed T-cell receptor beta chain usage and are mostly specific for cytotoxin-associated gene A, the distinctive oncoprotein injected by H pylori into host cells. As the infection progresses, we observe a loss of the TRM phenotype and replacement of CD8+ by CD4+ T cells, indicating a shift in the immune response during the chronic infection phase. CONCLUSIONS: Our results point toward a hitherto unknown role of CD8+ T-cell response in this bacterial infection, which may have important clinical implications for treatment and vaccination strategies against H pylori.


Asunto(s)
Infecciones por Helicobacter , Helicobacter pylori , Humanos , Animales , Ratones , Linfocitos T CD8-positivos , Linfocitos T CD4-Positivos , Estómago , Mucosa Gástrica/microbiología , Infecciones por Helicobacter/microbiología , Antígenos Bacterianos , Proteínas Bacterianas
8.
Eur J Immunol ; 53(3): e2250009, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36458456

RESUMEN

T cell ignorance is a specific form of immunological tolerance. It describes the maintenance of naivety in antigen-specific T cells in vivo despite the presence of their target antigen. It is thought to mainly play a role during the steady state, when self-antigens are presented in absence of costimulatory signals and at low density or to T cells of low affinity. In how far antigen-specific T cells can also remain clonally ignorant to foreign antigens, presented in the inflammatory context of systemic infection, remains unclear. Using single-cell in vivo fate mapping and high throughput flow cytometric enrichment, we find that high-affinity antigen-specific CD8+ T cells are efficiently recruited upon systemic infection. In contrast, most low-affinity antigen-specific T cells ignore the priming antigen and persist in the naïve state while remaining fully responsive to subsequent immunization with a high-affinity ligand. These data establish the widespread clonal ignorance of low-affinity T cells as a major factor shaping the composition of antigen-specific CD8+ T cell responses to systemic infection.


Asunto(s)
Autoantígenos , Linfocitos T CD8-positivos , Tolerancia Inmunológica , Diferenciación Celular
9.
Med Microbiol Immunol ; 212(3): 253-260, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37277539

RESUMEN

Clonal expansion and development of immunological memory are two hallmarks of adaptive immune responses. Resolving the intricate pathways that regulate cell cycle activity and lead to the generation of diverse effector and memory T cell subsets is essential for improving our understanding of protective T cell immunity. A deeper knowledge of cell cycle regulation in T cells also has translational implications for adoptive cell therapies and vaccinations against infectious diseases. Here, we summarize recent evidence for an early diversification of effector and memory CD8+ T cell fates and discuss how this process is coupled to discrete changes in division speed. We further review technical advances in lineage tracing and cell cycle analysis and outline how these techniques have shed new light on the population dynamics of CD8+ T cell responses, thereby refining our current understanding of the developmental organization of the memory T cell pool.


Asunto(s)
Linfocitos T CD8-positivos , Subgrupos de Linfocitos T , Diferenciación Celular , Activación de Linfocitos , Memoria Inmunológica/fisiología , Ciclo Celular
12.
Artículo en Inglés | MEDLINE | ID: mdl-33903160

RESUMEN

Memory differentiation of CD4 and CD8 T-cell populations has been extensively studied and many key molecular players and transcriptional networks have been identified. But how regulatory principles, identified on this population level, translate to immune responses that originate from single antigen-specific T cells is only now being elucidated. Here, we provide a short summary of the approaches used for mapping the fate of individual T cells and their progeny in vivo. We then highlight which major questions, with respect to memory T-cell differentiation, have been addressed by studying the development of single-cell-derived T-cell families during infection or vaccination. We discuss how fate decisions of single T cells are modulated by the affinity of their TCR and further shaped through a coregulation of T-cell differentiation and T-cell proliferation. These current findings indicate the early segregation into slowly dividing T central memory precursors (CMPs) and rapidly dividing non-CMPs, as a key event that separates the developmental paths of long- and short-lived T cells.


Asunto(s)
Diferenciación Celular , Memoria Inmunológica , Células T de Memoria/fisiología , Animales , Humanos , Análisis de la Célula Individual
13.
Nat Commun ; 11(1): 113, 2020 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-31913278

RESUMEN

While antigen-primed T cells proliferate at speeds close to the physiologic maximum of mammalian cells, T cell memory is maintained in the absence of antigen by rare cell divisions. The transition between these distinct proliferative programs has been difficult to resolve via population-based analyses. Here, we computationally reconstruct the proliferative history of single CD8+ T cells upon vaccination and measure the division speed of emerging T cell subsets in vivo. We find that slower cycling central memory precursors, characterized by an elongated G1 phase, segregate early from the bulk of rapidly dividing effector subsets, and further slow-down their cell cycle upon premature removal of antigenic stimuli. In contrast, curtailed availability of inflammatory stimuli selectively restrains effector T cell proliferation due to reduced receptivity for interleukin-2. In line with these findings, persistence of antigenic but not inflammatory stimuli throughout clonal expansion critically determines the later size of the memory compartment.


Asunto(s)
Linfocitos T CD8-positivos/citología , Diferenciación Celular , División Celular , Memoria Inmunológica , Subgrupos de Linfocitos T/citología , Animales , Linfocitos T CD8-positivos/inmunología , Ciclo Celular , Femenino , Interleucina-2/genética , Interleucina-2/inmunología , Ratones , Ratones Endogámicos C57BL , Subgrupos de Linfocitos T/inmunología
14.
Case Rep Dermatol ; 9(1): 140-144, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28559813

RESUMEN

Subcorneal pustular dermatosis (SCPD, Sneddon-Wilkinson disease) is a rare chronic-relapsing skin disorder that typically manifests as flaccid sterile pustules without systemic symptoms. Although the accumulation of neutrophils is acknowledged to be a hallmark of SCPD, its exact pathomechanism is still not known. Several chemotactic factors have been implicated in neutrophil recruitment and invasion, including the proinflammatory cytokine TNF-α. These findings correspond well with clinical reports of successful off-label use of TNF blocking agents in cases that were refractory to first-line therapy, mostly with dapsone. We report the case of a 29-year-old male with atypical and severe manifestation of SCPD that resolved after a single dose of infliximab. Consolidation was observed 1 day after treatment and regression of skin lesions occurred after a few days. Residual scarring and postlesional hyperpigmentation was seen at a 2-month follow-up appointment. The patient was initiated on a daily maintenance therapy with dapsone, which led to a drop in hemoglobin and had to be stopped. Upon development of small, scaly lesions, a maintenance therapy with infliximab was started and the patient has had no recurrence to date. Anti-TNF agents present a promising option for patients affected by severe SCPD. We review the reports of similar cases in the literature to date.

15.
Cell Rep ; 20(4): 806-818, 2017 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-28746867

RESUMEN

To what extent the lineage decisions of activated CD4+ T cells are determined by the quality of T cell receptor (TCR) ligation is incompletely understood. Here, we show that individual T cells expressing identical TCRs take highly variable fate decisions despite binding the same ligand. We identify a mathematical model that correctly captures this probabilistic behavior and allows one to formalize changes in TCR signal quality-due to cognate versus altered peptide ligation-as changes of lineage-specific proliferation and differentiation rates. We show that recall responses also adhere to this probabilistic framework requiring recruitment of multiple memory clones to provide reliable differentiation patterns. By extending our framework to simulate hypothetical TCRs of distinct binding strength, we reconstruct primary and secondary response patterns emerging from a polyclonal TCR repertoire in silico. Collectively, these data suggest that individual T cells harboring distinct TCRs generate overlapping primary differentiation patterns that segregate only upon repetitive immunization.


Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Animales , Diferenciación Celular/fisiología , Linaje de la Célula , Femenino , Receptores de Hialuranos/metabolismo , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Ratones , Ratones Endogámicos C57BL , Transducción de Señal/fisiología
16.
Science ; 340(6132): 630-5, 2013 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-23493420

RESUMEN

A core feature of protective T cell responses to infection is the robust expansion and diversification of naïve antigen-specific T cell populations into short-lived effector and long-lived memory subsets. By means of in vivo fate mapping, we found a striking variability of immune responses derived from individual CD8(+) T cells and show that robust acute and recall immunity requires the initial recruitment of multiple precursors. Unbiased mathematical modeling identifies the random integration of multiple differentiation and division events as the driving force behind this variability. Within this probabilistic framework, cell fate is specified along a linear developmental path that progresses from slowly proliferating long-lived to rapidly expanding short-lived subsets. These data provide insights into how complex biological systems implement stochastic processes to guarantee robust outcomes.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Inmunidad Celular , Memoria Inmunológica , Listeriosis/inmunología , Subgrupos de Linfocitos T/inmunología , Traslado Adoptivo , Animales , Diferenciación Celular , Linaje de la Célula , Proliferación Celular , Selección Clonal Mediada por Antígenos , Simulación por Computador , Inmunofenotipificación , Interferón gamma/biosíntesis , Interleucina-2/biosíntesis , Listeria monocytogenes , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Modelos Inmunológicos , Análisis de la Célula Individual , Procesos Estocásticos , Especificidad del Receptor de Antígeno de Linfocitos T
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