Suppressive function of regulatory T cells (Treg) is dependent on signaling of their antigen receptors triggered by cognate self, dietary, or microbial peptides presented on MHC II. However, it remains largely unknown whether distinct or shared repertoires of Treg TCRs are mobilized in response to different challenges in the same tissue or the same challenge in different tissues. Here we use a fixed TCRβ chain FoxP3-GFP mouse model to analyze conventional (eCD4) and regulatory (eTreg) effector TCRα repertoires in response to six distinct antigenic challenges to the lung and skin. This model shows highly 'digital' repertoire behavior with easy-to-track challenge-specific TCRα CDR3 clusters. For both eCD4 and eTreg subsets, we observe challenge-specific clonal expansions yielding homologous TCRα clusters within and across animals and exposure sites, which are also reflected in the draining lymph nodes but not systemically. Some CDR3 clusters are shared across cancer challenges, suggesting a response to common tumor-associated antigens. For most challenges, eCD4 and eTreg clonal response does not overlap. Such overlap is exclusively observed at the sites of certain tumor challenges, and not systematically, suggesting transient and local tumor-induced eCD4=>eTreg plasticity. This transition includes a dominant tumor-responding eCD4 CDR3 motif, as well as characteristic iNKT TCRα CDR3. In addition, we examine the homeostatic tissue residency of clonal eTreg populations by excluding the site of challenge from our analysis. We demonstrate that distinct CDR3 motifs are characteristic of eTreg cells residing in particular lymphatic tissues, regardless of the challenge. This observation reveals the tissue-resident, antigen-specific clonal Treg populations.

• MeSH
• buněčné klony MeSH
• CD4-pozitivní T-lymfocyty * MeSH
• myši MeSH
• peptidy MeSH
• receptory antigenů T-buněk genetika   MeSH
• regulační T-lymfocyty * MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

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.

• 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

• MeSH
• imunita MeSH
• imunitní systém fyziologie   patofyziologie   MeSH
• imunoterapie MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• alergologie a imunologie
• biologie
• fyziologie
• NLK Publikační typ
• kolektivní monografie

The development and differentiation of T helper (Th) cell subsets is a highly plastic process which is strictly regulated by cytokines. Here we show that the transforming growth factor β (TGF-β)-dependent differentiation programs are negatively regulated by interleukin-12 (IL-12). The development of TGF-β-induced regulatory T cells (iTregs) or TGF-β/IL-6 activated Th17 cells from purified mouse CD4(+)CD25(-) T cells, stimulated with monoclonal antibody anti-CD3, was abrogated in the presence of IL-12 and a different developmental program was established. On the molecular level, IL-12 inhibited the expression of the lineage specific transcription factors Foxp3 and RORγt in developing Tregs and Th17 cells, respectively. Moreover, IL-12 was able to alter the development of iTregs and Th17 cells even when added to the differentiating cells after 48h of the culture. The cells activated in the presence of TGF-β and IL-12 had an increased expression of the Th1 transcription factor T-bet, produced Th1 cytokines interferon γ and IL-2 and expressed IL-18 receptor and C-C chemokine receptor type 5 which are the phenotypic markers characteristic for Th1 cells. Furthermore, the cells activated in the presence of both TGF-β and IL-12, and not of TGF-β only, stimulated macrophages to produce nitric oxide. Altogether, these results indicate that IL-12 is a superior cytokine that has the ability to skew the already ongoing TGF-β-dependent iTreg or Th17 developmental program into Th1-like direction.

• MeSH
• buněčná diferenciace účinky léků   imunologie   MeSH
• buňky Th17 cytologie   účinky léků   imunologie   metabolismus   MeSH
• exprese genu účinky léků   imunologie   MeSH
• forkhead transkripční faktory genetika   imunologie   metabolismus   MeSH
• interferon gama genetika   imunologie   metabolismus   MeSH
• interleukin-12 imunologie   farmakologie   MeSH
• interleukin-2 genetika   imunologie   metabolismus   MeSH
• interleukin-6 genetika   imunologie   metabolismus   MeSH
• jaderné receptory - podrodina 1, skupina F, člen 3 genetika   imunologie   metabolismus   MeSH
• makrofágy cytologie   účinky léků   imunologie   MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• oxid dusnatý biosyntéza   MeSH
• receptory CCR5 genetika   imunologie   metabolismus   MeSH
• receptory interleukinu-18 genetika   imunologie   metabolismus   MeSH
• regulační T-lymfocyty cytologie   účinky léků   imunologie   metabolismus   MeSH
• signální transdukce účinky léků   imunologie   MeSH
• Th1 buňky cytologie   účinky léků   imunologie   metabolismus   MeSH
• transformující růstový faktor beta imunologie   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH