Project Details
Projekt
Age-dependent signals driving dendritic cells to promote type II immunity
Subject Area
Immunology
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 322359157
Allergic diseases often develop in early life and the incidence of childhood allergies is on the rise. Neonatal immune balance is essential for survival and establishment of healthy immunity in later life. In both mouse and man, the treatment of neonates with antibiotics is associated with increased susceptibility to allergy months or years later but the mechanisms by which commensal encounter influences immunity remain ill-defined. Conventional dendritic cells (cDCs) are key activators of T cells that critically contribute to type II immunity and pathogenic responses, such as allergy, by inducing type II T helper (Th) responses. In early life, cDCs exhibit qualitative differences compared to adult life, including lower expression of costimulatory molecules and an intrinsic Th2 bias, especially at barrier organs. As a result, cDCs in early life are often considered under-developed or functionally immature.cDCs exist as functionally distinct subsets, namely cDC1 and cDC2, with cDC being the predominant inducers of type II immunity. We have revisited cDC development and function in early life and found that during the neonatal period cDC2 exhibit a distinct hematopoietic origin and, like other myeloid and lymphoid cells, develop in waves. However, ontogenetically distinct cDC2 in early life are transcriptionally and functionally similar. Instead, exposure to different cytokine environments with age transcriptionally imprints cDC2 with distinct ability to induce T cell responses. Importantly and in contrast to current dogma, despite exhibiting age-dependent differences in cell function, cDC2 in early life are functionally competent to induce T cell responses.In this proposal we will define the age-dependent environmental signals that imprint cDC2 function with age and investigate how these signals alter the ability of cDC2 to promote type II immune responses. We hypothesize that the cytokine signals that imprint cDC function with age arise in response to the microbiome and that perturbation of early life microbial encounter can have a lasting impact on the ability of cDC2 to mediate type II immune responses. We will address these hypotheses using transcriptional profiling and functional analyses of cDC2 with age and upon disruption of early life microbial encounter. Additionally, we will use cDC lineage specific knock out mice to define the impact of specific cytokines on the ability of cDC2 to promote type II immunity with age. The proposed studies critically rely on collaborative interactions, as well as models and expertise on type II immunity available within the FOR 2599. Taken together our studies will shed light on the fundamental mechanisms underlying the age-dependent regulation of type II immunity.
DFG Programme
Research Units
