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1.
Immunity ; 56(9): 2021-2035.e8, 2023 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-37516105

RESUMO

Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. Here, we identified ketone bodies (KBs)-including ß-hydroxybutyrate (ßOHB) and acetoacetate (AcAc)-as essential fuels supporting CD8+ T cell metabolism and effector function. ßOHB directly increased CD8+ T effector (Teff) cell cytokine production and cytolytic activity, and KB oxidation (ketolysis) was required for Teff cell responses to bacterial infection and tumor challenge. CD8+ Teff cells preferentially used KBs over glucose to fuel the tricarboxylic acid (TCA) cycle in vitro and in vivo. KBs directly boosted the respiratory capacity and TCA cycle-dependent metabolic pathways that fuel CD8+ T cell function. Mechanistically, ßOHB was a major substrate for acetyl-CoA production in CD8+ T cells and regulated effector responses through effects on histone acetylation. Together, our results identify cell-intrinsic ketolysis as a metabolic and epigenetic driver of optimal CD8+ T cell effector responses.


Assuntos
Linfócitos T CD8-Positivos , Histonas , Ácido 3-Hidroxibutírico/metabolismo , Ácido 3-Hidroxibutírico/farmacologia , Acetilação , Histonas/metabolismo , Corpos Cetônicos , Animais , Camundongos
2.
Immunity ; 44(4): 860-74, 2016 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-27067057

RESUMO

The role of dendritic cells (DCs) in intestinal immune homeostasis remains incompletely defined. Here we show that mice lacking IRF8 transcription-factor-dependent DCs had reduced numbers of T cells in the small intestine (SI), but not large intestine (LI), including an almost complete absence of SI CD8αß(+) and CD4(+)CD8αα(+) T cells; the latter requiring ß8 integrin expression by migratory IRF8 dependent CD103(+)CD11b(-) DCs. SI homing receptor induction was impaired during T cell priming in mesenteric lymph nodes (MLN), which correlated with a reduction in aldehyde dehydrogenase activity by SI-derived MLN DCs, and inefficient T cell localization to the SI. These mice also lacked intestinal T helper 1 (Th1) cells, and failed to support Th1 cell differentiation in MLN and mount Th1 cell responses to Trichuris muris infection. Collectively these results highlight multiple non-redundant roles for IRF8 dependent DCs in the maintenance of intestinal T cell homeostasis.


Assuntos
Células Dendríticas/imunologia , Homeostase/imunologia , Fatores Reguladores de Interferon/metabolismo , Intestinos/imunologia , Linfócitos T Citotóxicos/imunologia , Células Th1/imunologia , Aldeído Desidrogenase/metabolismo , Animais , Apresentação de Antígeno/imunologia , Antígenos CD11/genética , Antígenos CD8/metabolismo , Diferenciação Celular/imunologia , Movimento Celular/imunologia , Células Cultivadas , Cadeias alfa de Integrinas/genética , Cadeias beta de Integrinas/metabolismo , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/imunologia , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Intestinos/citologia , Linfonodos/citologia , Linfonodos/imunologia , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Th1/citologia , Trichuris/imunologia
3.
Scand J Immunol ; 96(5): e13219, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37807915

RESUMO

The intestinal lamina propria (LP) contains distinct subsets of classical dendritic cells (cDC), each playing key non-redundant roles in intestinal immune homeostasis. Here, we show that glycoprotein 2 (GP2), a GPI-anchored protein and receptor for bacterial type-I fimbriae, is selectively expressed by CD103+CD11b+ cDC in the murine small intestine (SI). GP2 expression was induced on CD103+CD11b+ cDC within the SI-LP and was regulated by IRF4, TGFßR1- and retinoic acid signalling. Mice selectively lacking Gp2 on CD103+CD11b+ cDC (huLang-Cre.gp2fl/fl mice) had normal numbers and proportions of innate and adaptive immune cells in the SI-LP suggesting that GP2 expression by CD103+CD11b+ cDC is not required for intestinal immune homoeostasis.


Assuntos
Cadeias alfa de Integrinas , Intestinos , Camundongos , Animais , Mucosa Intestinal , Intestino Delgado , Transdução de Sinais , Células Dendríticas , Camundongos Endogâmicos C57BL
4.
J Exp Med ; 221(9)2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-39150482

RESUMO

Coordination of cellular metabolism is essential for optimal T cell responses. Here, we identify cytosolic acetyl-CoA production as an essential metabolic node for CD8 T cell function in vivo. We show that CD8 T cell responses to infection depend on acetyl-CoA derived from citrate via the enzyme ATP citrate lyase (ACLY). However, ablation of ACLY triggers an alternative, acetate-dependent pathway for acetyl-CoA production mediated by acyl-CoA synthetase short-chain family member 2 (ACSS2). Mechanistically, acetate fuels both the TCA cycle and cytosolic acetyl-CoA production, impacting T cell effector responses, acetate-dependent histone acetylation, and chromatin accessibility at effector gene loci. When ACLY is functional, ACSS2 is not required, suggesting acetate is not an obligate metabolic substrate for CD8 T cell function. However, loss of ACLY renders CD8 T cells dependent on acetate (via ACSS2) to maintain acetyl-CoA production and effector function. Together, ACLY and ACSS2 coordinate cytosolic acetyl-CoA production in CD8 T cells to maintain chromatin accessibility and T cell effector function.


Assuntos
ATP Citrato (pro-S)-Liase , Acetatos , Acetilcoenzima A , Linfócitos T CD8-Positivos , Cromatina , Camundongos Endogâmicos C57BL , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Animais , Cromatina/metabolismo , Acetilcoenzima A/metabolismo , ATP Citrato (pro-S)-Liase/metabolismo , ATP Citrato (pro-S)-Liase/genética , Camundongos , Acetatos/metabolismo , Acetato-CoA Ligase/metabolismo , Acetato-CoA Ligase/genética , Acetilação , Camundongos Knockout , Citosol/metabolismo , Histonas/metabolismo
5.
Cell Metab ; 34(9): 1298-1311.e6, 2022 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-35981545

RESUMO

How environmental nutrient availability impacts T cell metabolism and function remains poorly understood. Here, we report that the presence of physiologic carbon sources (PCSs) in cell culture medium broadly impacts glucose utilization by CD8+ T cells, independent of transcriptional changes in metabolic reprogramming. The presence of PCSs reduced glucose contribution to the TCA cycle and increased effector function of CD8+ T cells, with lactate directly fueling the TCA cycle. In fact, CD8+ T cells responding to Listeria infection preferentially consumed lactate over glucose as a TCA cycle substrate in vitro, with lactate enhancing T cell bioenergetic and biosynthetic capacity. Inhibiting lactate-dependent metabolism in CD8+ T cells by silencing lactate dehydrogenase A (Ldha) impaired both T cell metabolic homeostasis and proliferative expansion in vivo. Together, our data indicate that carbon source availability shapes T cell glucose metabolism and identifies lactate as a bioenergetic and biosynthetic fuel for CD8+ effector T cells.


Assuntos
Linfócitos T CD8-Positivos , Carbono , Linfócitos T CD8-Positivos/metabolismo , Carbono/metabolismo , Glucose/metabolismo , Ácido Láctico/metabolismo , Nutrientes
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