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1.
J Immunol ; 206(12): 2875-2887, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34049970

RESUMO

The quality of T cell responses depends on the lymphocytes' ability to undergo clonal expansion, acquire effector functions, and traffic to the site of infection. Although TCR signal strength is thought to dominantly shape the T cell response, by using TCR transgenic CD4+ T cells with different peptide:MHC binding affinity, we reveal that TCR affinity does not control Th1 effector function acquisition or the functional output of individual effectors following mycobacterial infection in mice. Rather, TCR affinity calibrates the rate of cell division to synchronize the distinct processes of T cell proliferation, differentiation, and trafficking. By timing cell division-dependent IL-12R expression, TCR affinity controls when T cells become receptive to Th1-imprinting IL-12 signals, determining the emergence and magnitude of the Th1 effector pool. These findings reveal a distinct yet cooperative role for IL-12 and TCR binding affinity in Th1 differentiation and suggest that the temporal activation of clones with different TCR affinity is a major strategy to coordinate immune surveillance against persistent pathogens.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Mycobacterium bovis/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Células Cultivadas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos
2.
Cell Rep ; 41(7): 111638, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36384123

RESUMO

Modulation of individual macronutrients or caloric density is known to regulate host resistance to infection in mice. However, the impact of diet composition, independent of macronutrient and energy content, on infection susceptibility is unclear. We show that two laboratory rodent diets, widely used as standard animal feeds and experimental controls, display distinct abilities in supporting mice during influenza infection. Mice placed on the highly processed AIN93G showed increased mortality to infection compared with those on a grain-based chow diet, suggesting a detrimental role for highly processed food in host defense. We further demonstrate that the heightened susceptibility of AIN93G-fed mice was associated with the failure in homeostasis restoration mediated by the cytokine interferon (IFN)-γ. Our findings show that diet composition calibrates host survival threshold by regulating adaptive homeostasis and highlights a pivotal role for extrinsic signals in host phenotype and outcome of host-pathogen interaction.


Assuntos
Influenza Humana , Camundongos , Animais , Humanos , Nutrientes , Dieta
3.
Cell Rep ; 29(11): 3539-3550.e4, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31825834

RESUMO

Interferons (IFN) are pleiotropic cytokines essential for defense against infection, but the identity and tissue distribution of IFN-responsive cells in vivo are poorly defined. In this study, we generate a mouse strain capable of reporting IFN-signaling activated by all three types of IFNs and investigate the spatio-temporal dynamics and identity of IFN-responding cells following IFN injection and influenza virus infection. Despite ubiquitous expression of IFN receptors, cellular responses to IFNs are highly heterogenous in vivo and are determined by anatomical site, cell type, cellular preference to individual IFNs, and activation status. Unexpectedly, type I and II pneumocytes, the primary target of influenza infection, exhibit striking differences in the strength and temporal dynamics of IFN signaling associated with differential susceptibility to the viral infection. Our findings suggest that time- and cell-type-dependent integration of distinct IFN signals govern the specificity and magnitude of IFN responses in vivo.


Assuntos
Interferons/metabolismo , Infecções por Orthomyxoviridae/metabolismo , Transdução de Sinais , Células Epiteliais Alveolares/metabolismo , Animais , Células Cultivadas , Feminino , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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