The importance of cellular metabolic adaptation in inducing robust T cell responses is well established. However, the mechanism by which T cells link information regarding nutrient supply to clonal expansion and effector function is still enigmatic. Herein, we report that the metabolic sensor adenosine monophosphate-activated protein kinase (AMPK) is a critical link between cellular energy demand and translational activity and, thus, orchestrates optimal expansion of T cells in vivo. AMPK deficiency did not affect T cell fate decision, activation, or T effector cell generation; however, the magnitude of T cell responses in murine in vivo models of T cell activation was markedly reduced. This impairment was global, as all T helper cell subsets were similarly sensitive to loss of AMPK which resulted in reduced T cell accumulation in peripheral organs and reduced disease severity in pathophysiologically as diverse models as T cell transfer colitis and allergic airway inflammation. T cell receptor repertoire analysis confirmed similar clonotype frequencies in different lymphoid organs, thereby supporting the concept of a quantitative impairment in clonal expansion rather than a skewed qualitative immune response. In line with these findings, in-depth metabolic analysis revealed a decrease in T cell oxidative metabolism, and gene set enrichment analysis indicated a major reduction in ribosomal biogenesis and mRNA translation in AMPK-deficient T cells. We, thus, provide evidence that through its interference with these delicate processes, AMPK orchestrates the quantitative, but not the qualitative, manifestation of primary T cell responses in vivo.

• Klíčová slova
• AMPK, T cell, cellular metabolism, translation,
• MeSH
• adenylátkinasa genetika   metabolismus   MeSH
• aktivace lymfocytů MeSH
• buňky Th17 fyziologie   MeSH
• CD4-pozitivní T-lymfocyty MeSH
• DNA vazebné proteiny genetika   metabolismus   MeSH
• fyziologická adaptace MeSH
• kolitida imunologie   MeSH
• messenger RNA genetika   metabolismus   MeSH
• myši knockoutované MeSH
• myši MeSH
• převzatá imunita MeSH
• regulace genové exprese enzymů MeSH
• regulační T-lymfocyty fyziologie   MeSH
• T-lymfocyty pomocné-indukující fyziologie   MeSH
• Th1 buňky fyziologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenylátkinasa MeSH
• DNA vazebné proteiny MeSH
• messenger RNA MeSH
• Rag2 protein, mouse MeSH Prohlížeč

Crohn's disease is linked to a decreased diversity in gut microbiota composition as a potential consequence of an impaired anti-microbial response and an altered polarization of T helper cells. Here, we evaluated the immunomodulatory properties of two potential probiotic strains, namely a Bifidobacterium animalis spp. lactis Bl 5764 and a Lactobacillus reuteri Lr 5454 strains. Both strains improved colitis triggered by either 2,4,6-trinitrobenzenesulfonic acid (TNBS) or Citrobacter rodentium infection in mice. Training of dendritic cells (DC) with Lr 5454 efficiently triggered IL-22 secretion and regulatory T cells induction in vitro, while IL-17A production by CD4+ T lymphocytes was stronger when cultured with DCs that were primed with Bl 5764. This strain was sufficient for significantly inducing expression of antimicrobial peptides in vivo through the Crohn's disease predisposing gene encoding for the nucleotide-binding oligomerization domain, containing protein 2 (NOD2). In contrast, NOD2 was dispensable for the impact on antimicrobial peptide expression in mice that were monocolonized with Lr 5454. In conclusion, our work highlights a differential mode of action of two potential probiotic strains that protect mice against colitis, providing the rational for a personalized supportive preventive therapy by probiotics for individuals that are genetically predisposed to Crohn's disease.

• MeSH
• antiflogistika nesteroidní farmakologie   MeSH
• Bifidobacterium animalis * MeSH
• Citrobacter rodentium patogenita   MeSH
• dendritické buňky fyziologie   MeSH
• enterobakteriální infekce mikrobiologie   MeSH
• gnotobiologické modely MeSH
• kolitida chemicky indukované   mikrobiologie   patologie   terapie   MeSH
• kyselina trinitrobenzensulfonová toxicita   MeSH
• Limosilactobacillus reuteri * MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• probiotika farmakologie   MeSH
• proteiny asociované s pankreatitidou genetika   MeSH
• regulační T-lymfocyty fyziologie   MeSH
• střevní mikroflóra MeSH
• T-lymfocyty pomocné-indukující fyziologie   MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antiflogistika nesteroidní MeSH
• kyselina trinitrobenzensulfonová MeSH
• proteiny asociované s pankreatitidou MeSH
• Reg3b protein, mouse MeSH Prohlížeč

Protective immunity against murine malaria infection depends largely on the establishment of effective Th1 immune response during the early stages of infection. Experimental data suggest that the death of Plasmodium yoelii 17XL (Py 17XL) susceptible BALB/c mice results from the suppression of Th1 immune response mediated by CD4+CD25+Foxp3+ regulatory T cells (Tregs). However, the mechanism by which Tregs regulate Th1 immune response is poorly understood. Since immunity is initiated by dendritic cells (DCs), we analysed DC responses to Py 17XL in control and Treg-depleted BALB/c mice. Myeloid DC proliferation, phenotypic maturation and interleukin-12 (IL-12) production were strongly inhibited in control BALB/c mice. In contrast, plasmacytoid DC proliferation and IL-10 production were strongly enhanced in control BALB/c mice. In-vivo depletion of Tregs resulted in significantly reversed inhibition of DC response, which may contribute to the establishment of Th1 immune response, indicating that Tregs contribute to the suppression of Th1 immune response during malaria. These findings suggest Tregs contribute to prevent Th1 immune response establishment during the early stage of Py 17XL infection by inhibiting DC response.

• MeSH
• dendritické buňky fyziologie   MeSH
• forkhead transkripční faktory genetika   metabolismus   MeSH
• malárie imunologie   parazitologie   MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• Plasmodium yoelii MeSH
• regulační T-lymfocyty fyziologie   MeSH
• Th1 buňky fyziologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• forkhead transkripční faktory MeSH
• Foxp3 protein, mouse MeSH Prohlížeč

The stimulation rate with PHA of murine spleen cells increases after removal of glass-adherent cells from the total spleen population. Unfractionated spleen population from HC treated mice suppresses the response to PHA of glass non-adherent cells from untreated animals only 24-48 h after HC treatment. From the third day on after the treatment the suppressive effect disappears.

• MeSH
• fytohemaglutininy farmakologie   MeSH
• hydrokortison farmakologie   MeSH
• myši MeSH
• regulační T-lymfocyty fyziologie   MeSH
• slezina cytologie   účinky léků   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fytohemaglutininy MeSH
• hydrokortison MeSH