RESUMO
Since 2014, cases of acute flaccid myelitis (AFM) have been reported in the United States in increasing numbers biennially, occurring in the late summer and early fall. Although there is unlikely to be a single causative agent of this syndrome, non-polio enteroviruses, including enterovirus D-68 (EV-D68), have had epidemiological and laboratory associations with AFM. Much remains to be known about AFM and AFM-associated enteroviruses, including disease pathogenesis and the best strategies for development of therapeutics or preventive modalities including vaccines. To catalyze research that addresses these scientific and clinical gaps, the National Institute of Allergy and Infectious Diseases convened a workshop entitled "AFM Preparedness: Addressing EV-D68 and Other AFM-Associated Enteroviruses" on 19-20 February 2020.
Assuntos
Viroses do Sistema Nervoso Central , Enterovirus Humano D , Mielite , Doenças Neuromusculares , Humanos , Estados UnidosRESUMO
The intracellular signaling mechanisms regulating the generation and long-term persistence of memory T cells in vivo remain unclear. In this study, we used mouse models with conditional deletion of the key T cell receptor (TCR)-coupled adaptor molecule SH2-domain-containing phosphoprotein of 76 kDa (SLP-76), to analyze signaling mechanisms for memory CD4 T cell generation, maintenance, and homeostasis. We found that ablation of SLP-76 expression after T cell priming did not inhibit generation of phenotypic effector or memory CD4 T cells; however, the resultant SLP-76-deficient memory CD4 T cells could not produce recall cytokines in response to TCR-mediated stimulation and showed decreased persistence in vivo. In addition, SLP-76-deficient memory CD4 T cells exhibited reduced steady-state homeostasis and were impaired in their ability to homeostatically expand in vivo in response to the gamma(c) cytokine IL-7, despite intact proximal signaling through the IL-7R-coupled JAK3/STAT5 pathway. Direct in vivo deletion of SLP-76 in polyclonal memory CD4 T cells likewise led to impaired steady-state homeostasis as well as impaired homeostatic responses to IL-7. Our findings demonstrate a dominant role for SLP-76-dependent TCR signals in regulating turnover and perpetuation of memory CD4 T cells and their responses to homeostatic cytokines, with implications for the selective survival of memory CD4 T cells following pathogen exposure, vaccination, and aging.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Linfócitos T CD4-Positivos/imunologia , Citocinas/fisiologia , Fosfoproteínas/fisiologia , Linfócitos T/imunologia , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Regulação para Baixo , Técnicas de Transferência de Genes , Genes Reporter , Homeostase/genética , Homeostase/imunologia , Memória Imunológica , Interleucina-7/farmacologia , Proteínas Luminescentes/genética , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Modelos Animais , Fosfoproteínas/deficiência , Fosfoproteínas/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologiaRESUMO
The memory immune response forms the basis for protective immunity and is orchestrated by long-lived memory T lymphocytes. Memory T cells mediate potent and rapid effector function upon secondary challenge, and migrate to diverse peripheral sites, resulting in efficacious clearance of pathogens before the onset of disease. However, these robust memory T cell functions and diverse homing capacities can also lead to immunopathology in viral infections, autoimmunity, and transplantation. Elucidating mechanisms controlling memory T cell generation and recall responses therefore has broad clinical and immunological relevance. In this review, we highlight advances in the past year on dissecting the processes of memory generation, recall capacity, and regulation of memory T cell responses. We discuss the past year's studies focused on identifying pathways and precursors for memory development at both the priming and effector stage, and how the earliest events in T cell activation may have far-ranging influences on the resultant memory T cell population. We also describe results on the biochemical and molecular control of the distinct and immediate effector functions of memory T cells and their implications for immunotherapies. Finally, we present recent technological advances in T cell tracking and imagery and how they may be applied to provide new insight into the complex nature of the memory immune response.
Assuntos
Memória Imunológica/imunologia , Linfócitos T/imunologia , Animais , Diferenciação Celular , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Modelos BiológicosRESUMO
Mechanisms for the generation of memory CD4 T cells and their delineation into diverse subsets remain largely unknown. In this study, we demonstrate in two Ag systems, divergent generation of heterogeneous memory CD4 T cells from activated precursors in distinct differentiation stages. Specifically, we show that influenza hemagglutinin- and OVA-specific CD4 T cells activated for 1, 2, and 3 days, respectively, exhibit gradations of differentiation by cell surface phenotype, IFN-gamma production, and proliferation, yet all serve as direct precursors for functional memory CD4 T cells when transferred in vivo into Ag-free mouse hosts. Using a conversion assay to track the immediate fate of activated precursors in vivo, we show that day 1- to 3-activated cells all rapidly convert from an activated phenotype (CD25(high)IL-7R(low)CD44(high)) to a resting memory phenotype (IL-7R(high)CD25(low)CD44(high)) 1 day after antigenic withdrawal. Paradoxically, stable memory subset delineation from undifferentiated (day 1- to 2-activated) precursors was predominantly an effector memory (CD62L(low)) profile, with an increased proportion of central memory (CD62L(high)) T cells arising from more differentiated (day 3-activated) precursors. Our findings support a divergent model for generation of memory CD4 T cells directly from activated precursors in multiple differentiation states, with subset heterogeneity maximized by increased activation and differentiation during priming.