Antigen-presenting cells (APCs) are master regulators of the immune response by directly interacting with T cells to orchestrate distinct functional outcomes. Several types of professional APC exist, including conventional dendritic cells, B cells and macrophages, and numerous other cell types have non-classical roles in antigen presentation, such as thymic epithelial cells, endothelial cells and granulocytes. Accumulating evidence indicates the presence of a new family of APCs marked by the lineage-specifying transcription factor retinoic acid receptor-related orphan receptor-γt (RORγt) and demonstrates that these APCs have key roles in shaping immunity, inflammation and tolerance, particularly in the context of host-microorganism interactions. These RORγt+ APCs include subsets of group 3 innate lymphoid cells, extrathymic autoimmune regulator-expressing cells and, potentially, other emerging populations. Here, we summarize the major findings that led to the discovery of these RORγt+ APCs and their associated functions. We discuss discordance in recent reports and identify gaps in our knowledge in this burgeoning field, which has tremendous potential to advance our understanding of fundamental immune concepts.
- MeSH
- antigen prezentující buňky metabolismus MeSH
- endoteliální buňky MeSH
- jaderné receptory - podrodina 1, skupina F, člen 3 * metabolismus MeSH
- lidé MeSH
- lymfocyty * MeSH
- přirozená imunita MeSH
- transportní proteiny metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The autoimmune regulator (Aire) serves an essential function for T cell tolerance by promoting the "promiscuous" expression of tissue antigens in thymic epithelial cells. Aire is also detected in rare cells in peripheral lymphoid organs, but the identity of these cells is poorly understood. Here, we report that Aire protein-expressing cells in lymph nodes exhibit typical group 3 innate lymphoid cell (ILC3) characteristics such as lymphoid morphology, absence of "classical" hematopoietic lineage markers, and dependence on RORγt. Aire+ cells are more frequent among lineage-negative RORγt+ cells of peripheral lymph nodes as compared with mucosa-draining lymph nodes, display a unique Aire-dependent transcriptional signature, express high surface levels of MHCII and costimulatory molecules, and efficiently present an endogenously expressed model antigen to CD4+ T cells. These findings define a novel type of ILC3-like cells with potent APC features, suggesting that these cells serve a function in the control of T cell responses.
- MeSH
- adhezní molekula epiteliálních buněk metabolismus MeSH
- antigen prezentující buňky imunologie MeSH
- antigeny CD11 metabolismus MeSH
- fenotyp MeSH
- genetická transkripce MeSH
- histokompatibilita - antigeny třídy II metabolismus MeSH
- jaderné receptory - podrodina 1, skupina F, člen 3 metabolismus MeSH
- lymfatické uzliny cytologie MeSH
- lymfocyty imunologie metabolismus MeSH
- myši inbrední BALB C MeSH
- myši knockoutované MeSH
- myši MeSH
- přirozená imunita MeSH
- regulace genové exprese MeSH
- transkripční faktory genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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