Tissue residency is considered a defining feature of the innate lymphoid cell (ILC) populations located within mucosal and adipose tissues. ILCs are also present within all lymphoid tissues, but whether ILCs migrate between lymphoid and nonlymphoid sites and in what context is poorly understood. To determine whether migratory ILCs exist within peripheral lymph nodes (LNs), we labeled all cells within the brachial LN (bLN) of transgenic mice expressing a photoconvertible fluorescent protein by direct exposure to light. Tracking of cellular changes in the labeled LN revealed the gradual migration of new ILCs into the tissue, balanced by egress of ILCs dependent on sphingosine-1-phosphate receptors. Most of the migratory ILCs were ILC1s, entering LNs directly from the circulation in a CD62L- and CCR7-dependent manner and thus behaving like conventional natural killer (cNK) cells. Upon egress, both ILC1s and cNK cells were found to recirculate through peripheral LNs. A distinct population of migratory ILC2s were detected in the LN, but most of the ILC3s were tissue resident. Functionally, both migratory and resident ILC1s within LNs were able to rapidly produce IFN-γ to support the generation of robust TH1 T cell responses after immunization. Thus, migratory and resident ILC populations exist within peripheral LNs, with ILC1s, akin to cNK cells, able to traffic into these tissues where they can contribute to the initiation of adaptive immunity.
Conventional dendritic cells (cDC) are key activators of naive T cells, and can be targeted in adults to induce adaptive immunity, but in early life are considered under-developed or functionally immature. Here we show that, in early life, when the immune system develops, cDC2 exhibit a dual hematopoietic origin and, like other myeloid and lymphoid cells, develop in waves. Developmentally distinct cDC2 in early life, despite being distinguishable by fate mapping, are transcriptionally and functionally similar. cDC2 in early and adult life, however, are exposed to distinct cytokine environments that shape their transcriptional profile and alter their ability to sense pathogens, secrete cytokines and polarize T cells. We further show that cDC2 in early life, despite being distinct from cDC2 in adult life, are functionally competent and can induce T cell responses. Our results thus highlight the potential of harnessing cDC2 for boosting immunity in early life.
When dormant naïve T cells first become activated by antigenpresenting cells, they express the autocrine growth factor IL-2 which transforms them into rapidly dividing effector T cells. During this process, hundreds of genes undergo epigenetic reprogramming for efficient activation, and also for potential reactivation after they return to quiescence as memory T cells. However, the relative contributions of IL-2 and T cell receptor signaling to this process are unknown. Here, we show that IL-2 signaling is required to maintain open chromatin at hundreds of gene regulatory elements, many of which control subsequent stimulus-dependent alternative pathways of T cell differentiation. We demonstrate that IL-2 activates binding of AP-1 and STAT5 at sites that can subsequently bind lineage-determining transcription factors, depending upon what other external factors exist in the local T cell environment. Once established, priming can also be maintained by the stroma-derived homeostatic cytokine IL-7, and priming diminishes if Il7r is subsequently deleted in vivo. Hence, IL-2 is not just a growth factor; it lays the foundation for T cell differentiation and immunological memory.
Angeborene lymphoide Zellen (ILCs, engl. für Innate Lymphoid Cells) bilden eine kürzlich beschriebene Familie von Effektorzellen des angeborenen Immunsystems, die in verschiedenste immunologische Prozesse involviert sind. ILCs fehlen somatisch rekombinierte Antigenrezeptoren und können aufgrund ihrer Master-Transkriptionsfaktoren und Effektorfunktionen in drei Hauptgruppen eingeteilt werden. In der Embryonalentwicklung spielt ein spezifisches Mitglied der Typ 3 ILCs, sogenannte LTi (engl. für Lymphoid Tissue inducer) Zellen, eine zentrale Rolle in der Entwicklung von Lymphknoten. Wie die gesamte ILC3 Familie, sind auch LTi Zellen abhängig von dem Master-Transkriptionsfaktor ROR t, was sich in ROR t-defizienten Mäuse nicht nur durch die Abwesenheit aller ILC3, sondern makroskopisch auch durch fehlende Lymphknoten äußert. ILC3 persistieren bis ins Erwachsenenalter und befinden sich hauptsächlich im Darmgewebe und den assoziierten mesenterialen Lymphknoten, wo sie die Homöostase der Barrierefunktionen, Immunüberwachung, sowie die Typ-3-Gewebeimmunität unterstützen. Während postnatale Ko-expression der Transkriptionsfaktoren T-bet und ROR t in spezifischen ILC3-Subpopulationen und deren Bedeutung für Differenzierung, Phänotyp und Funktionen fest etabliert sind, ist der Einfluss von T-bet in fötalen ILC3 und auf die Generation von Lymphknoten noch unbekannt. Um diese Mechanismen genau zu untersuchen, wurden fötale ILCs mittels Einzelzell-RNA-Sequenzierung detailliert charakterisiert, wodurch eine unerwartete Heterogenität innerhalb der ILC3 mit T-bet-exprimierenden Zellen aufgedeckt wurde. Außerdem wurden PLZF + ILC-Vorläufer (ILCP, engl. für Innate Lymphoid Cell Precursor) im sich entwickelnden Darm nachgewiesen, was darauf hindeutet, dass der embryonale Darm eine aktive Differenzierungsnische für ILCs während der frühen Entwicklung darstellt. Weiterhin, bes ätigen verschiedene Mausmodelle eine Schlüsselrolle für T-bet in der Regulation der ILC-Differenzierung und der Entstehung von Lymphknoten. Im Detail konnte gezeigt werden, dass die zusätzliche genetische Ablation von T-bet in ROR tdefizienten Mäusen Differenzierungsentscheidungen in fötalen ILCP zentral beeinflusst. Die Abwesenheit von T-bet in ILCP ermöglichte die Akkumulation von ILCP mit LTi-Aktivität, wodurch die Organogenese von Lymphknoten, unabhängig von ROR t wiederhergestellt wurde. PLZF + ILCP von ROR t/T-bet-Doppeldefizienten Mäusen bestanden bis ins Erwachsenenalter, wo diese Zellen die Darmbarrierefunktionen durch Produktion von IL-22 wiederherstellten. Darüber hinaus erwies sich ROR als entscheidend für die Entwicklung von PLZF + ILCP und die damit verbundene Bildung von Lymphknoten. Insgesamt enthüllen diese Ergebnisse eine neue Rolle für T-bet und ROR in der embryonalen ILC-Differenzierung und der Lymphknoten-Organogenese, und decken die antagonistische Funktion von ROR t innerhalb der differenzierenden ILCP auf, T-bet entgegenzuwirken. Altogether, these data unveil a novel role for T-bet and ROR in embryonic ILC differentiation and LN organogene...
The OX40-OX40L pathway provides crucial co-stimulatory signals for CD4 T cell responses, however the precise cellular interactions critical for OX40L provision in vivo and when these occur, remains unclear. Here, we demonstrate that provision of OX40L by dendritic cells (DCs), but not T cells, B cells nor group 3 innate lymphoid cells (ILC3s), is critical specifically for the effector Th1 response to an acute systemic infection with Listeria monocytogenes (Lm). OX40L expression by DCs is regulated by cross-talk with NK cells, with IFNγ signalling to the DC to enhance OX40L in a mechanism conserved in both mouse and human DCs. Strikingly, DC expression of OX40L is redundant in a chronic intestinal Th1 response and expression by ILC3s is necessary. Collectively these data reveal tissue specific compartmentalisation of the cellular provision of OX40L and define a mechanism controlling DC expression of OX40L in vivo.
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