NFATc2 and NFATc3 transcription factors play a crucial role in suppression of CD4+ T lymphocytes by CD4+ CD25+ regulatory T cells

The phenotype of NFATc2−/− c3−/− (double knockout [DKO]) mice implies a disturbed regulation of T cell responses, evidenced by massive lymphadenopathy, splenomegaly, and autoaggressive phenomena. The population of CD4+ CD25+ T cells from DKO mice lacks regulatory capacity, except a small subpopulation that highly expresses glucocorticoid-induced tumor necrosis factor receptor family–related gene (GITR) and CD25. However, neither wild-type nor DKO CD4+ CD25+ regulatory T cells (T reg cells) are able to suppress proliferation of DKO CD4+ CD25− T helper cells. Therefore, combined NFATc2/c3 deficiency is compatible with the development of CD4+ CD25+ T reg cells but renders conventional CD4+ T cells unresponsive to suppression, underlining the importance of NFAT proteins for sustaining T cell homeostasis

Die kutane murine Mastzelle als Initiator angeborener und adaptiver Immunreaktionen der Haut

Für lange Zeit wurde die Mastzelle nur als Effektorzelle im Rahmen von Erkrankungen des atopischen Formenkreises gesehen. Erst lange Zeit nach ihrer ersten Beschreibung konnte gezeigt werden, dass die Mastzelle einen wichtigen Beitrag zur Abwehr von Pathogenen leistet. Dies wird vor allem durch Wege der alternativen Mastzellaktivierung, z.B. über Toll- like Rezeptoren, ermöglicht. In dieser Arbeit sollte daher zunächst die mögliche Funktion der Mastzelle bei der durch den synthetischen TLR7- Liganden Imiquimod induzierten Entzündungsreaktion der Haut und der Auswanderung von Langerhans Zellen in einem Mausmodell untersucht werden. Beide Reaktion waren dabei von Mastzellen abhängig sind. Für die frühe und schnelle Induktion der Entzündungsreaktion zeigten sich vor allem die Mastzellcytokine IL-1 und TNF-α verantwortlich. Bei der Auswanderung der Langerhans Zellen hingegen spielt das Mastzell-IL1 eine entscheidende Rolle. Imiquimod wurde in Form der Creme Aldara bereits erfolgreich zur transkutanen Immunisierung (TCI) in Mausversuchen verwendet. Da die oben beschriebenen Reaktionen, welche durch Imiquimod vermittelt werden, eine deutliche Abhängigkeit von Mastzellen zeigten, sollte nun auch die Funktion der Mastzelle bei der Entstehung einer adaptiven Immunantwort am Modell der transkutanen Immunisierung untersucht werden. Der Immunisierungserfolg und damit die Entstehung einer adaptiven Immunantwort konnte auch hier auf die Anwesenheit von Mastzellen zurückgeführt werden. Mastzellen können somit als ein weiteres wichtiges Bindeglied zwischen angeborener und erworbener Immunität gesehen werden und können so einen entscheidenden Einfluß auf die Entstehung einer adaptiven Immunantwort nehmen.Until resently, mast cells were known as effector cells of adaptive immune responses, especially in allergic reactions and mucosal immunity against some parasites. Murine dermal mast cells, activated by local administration of a synthetic TLR7 ligand imiquimod, are essential to initiate an early inflammatory reaction in the skin. These fast and early inflamation depends on mast cell-derived cytokines IL-1 and TNF-α. Mast cells, activated by TLR7 ligation, are also able to promote the emigration of Langerhans cells. In this process, mast cell IL-1 but not TNF-α seems to play an important role. Imiquimod could be used as an adjuvant for transcutaneous peptide immunization. As a consequence from the results mentioned above, we could demonstrate that transcutaneous immunization and therewith the development of an adaptive immune response is severely impaired in mast cell-deficient mice. These findings demonstrate the potent versability of alternatively activated mast cells at the interface of innate and adaptive immunity, whereby they can exert a wide influence on the development of an adaptive immune response

The late endosomal adaptor molecule p14 (LAMTOR2) represents a novel regulator of langerhans cell homeostasis

Langerhans cells (LCs) are dendritic cells (DCs) residing in epithelia, where they critically regulate immunity and tolerance. The p14 adaptor molecule is part of the late endosomal/LAMTOR (lysosomal adaptor and mitogen-activated protein kinase and mammalian target of rapamycin [mTOR] activator/regulator) complex, thereby contributing to the signal transduction of the extracellular signaling-regulated kinase (ERK) and the mTOR cascade. Furthermore, p14 represents an important regulator for endosomal sorting processes within the cell. Mutated, dysfunctional p14 leads to a human immunodeficiency disorder with endosomal/lysosomal defects in immune cells. Because p14 participates in the regulation of endosomal trafficking, growth factor signaling, and cell proliferation, we investigated the role of p14 in mouse DCs/LCs using a conditional knockout mouse model. p14-deficient animals displayed a virtually complete loss of LCs in the epidermis early after birth due to impaired proliferation and increased apoptosis of LCs. Repopulation analysis after application of contact sensitizer leads to the recruitment of a transient LC population, predominantly consisting of short-term LCs. The underlying molecular mechanism involves the p14-mediated disruption of the LAMTOR complex which results in the malfunction of both ERK and mTOR signal pathways. Hence, we conclude that p14 acts as a novel and essential regulator of LC homeostasis in vivo

Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression

Naturally occurring regulatory T cells (T reg cells) are a thymus-derived subset of T cells, which are crucial for the maintenance of peripheral tolerance by controlling potentially autoreactive T cells. However, the underlying molecular mechanisms of this strictly cell contact-dependent process are still elusive. Here we show that naturally occurring T reg cells harbor high levels of cyclic adenosine monophosphate (cAMP). This second messenger is known to be a potent inhibitor of proliferation and interleukin 2 synthesis in T cells. Upon coactivation with naturally occurring T reg cells the cAMP content of responder T cells is also strongly increased. Furthermore, we demonstrate that naturally occurring T reg cells and conventional T cells communicate via cell contact-dependent gap junction formation. The suppressive activity of naturally occurring T reg cells is abolished by a cAMP antagonist as well as by a gap junction inhibitor, which blocks the cell contact-dependent transfer of cAMP to responder T cells. Accordingly, our results suggest that cAMP is crucial for naturally occurring T reg cell-mediated suppression and traverses membranes via gap junctions. Hence, naturally occurring T reg cells unexpectedly may control the immune regulatory network by a well-known mechanism based on the intercellular transport of cAMP via gap junctions