FOR2599Project 3

Age-dependent signals driving dendritic cells to promote type II immunity

Barbara Schraml-Schotta, Biomedical Center, Walter-Brendel-Centre of Experimental Medicine, LMU Munich

Allergic diseases often develop in early life and the incidence of childhood allergies continues  to rise. cDCs are key activators of T cells that critically determine the outcome of allergen encounter. In early life, cDCs exhibit qualitative differences compared to adult life, including an intrinsic bias to stimulate type II immunity, which promotes allergic responses by inducing a bias towards Th2 effector and memory responses. However, the signals that regulate cDC function with age remain poorly defined. Microbiome-derived signals and metabolites act as important rheostats for immunoregulation and altering microbial encounter in early life can have lasting influence on the development of allergic diseases. Commensally-derived signals can impact cDC function, but how neonatal commensal encounter influences cDC2, the main cDC subtype to promote type II immunity, has not been investigated. We investigate how perturbing the neonatal microbial encounter affects cDC2  transcriptional profiles and function in early and adult life. Our goal is to generate a transcriptional atlas of gene expression in cDC2 with age allowing us to determine how cDC2 subset composition and transcriptional profiles change with age and in different organs. These experiments will shed light on the mechanisms, by which commensal microbes influence susceptibility to allergic disease in adulthood. Because preliminary data indicate that age dependent cytokine environments, possibly in response to commensal microbes, imprint cDC2 function, we will use mice with genetic deficiency in cytokine signalling and cDC lineage specific knock out mice to gain mechanistic insights into the regulation of DC2 function with age.

Selected publications

Salei N, Ji X, Pakalniškytė D, Kuentzel V, Rambichler S, Li N, Moser M, Steiger K, Buch T, Ander HJ, Schraml BU. Selective depletion of a CD64 expressing phagocyte subset mediates protection against toxic kidney injury and failure. Proceedings of the National Academy of Sciences.  in press, IF: 11,2 (2020).

Papaioannou NE, Salei N, Rambichler S, Ravi K, Popovic J, Küntzel V, Lehmann CHK, Fiancette R, Salvermoser J, Gajdasik DW, Mettler R, Messerer D, Carrelha J, Ohnmacht C, Haller D, Stumm R, Straub T, Jacobsen SEW, Schulz C, Withers DR, Schotta G, Dudziak D, Schraml BU2021. Environmental signals rather than layered ontogeny imprint the function of type 2 conventional dendritic cells in young and adult mice. Nature Communications. 21 (464).

Salei N, Rambichler S, Salvermoser J, Papaioannou NE, Schuchert R, Pakalniškytė D, Na Li, Marschner JA,  Lichtnekert J, Stremmel C, Cernilogar FM, Salvermoser M, Walzog B, Straub T, Schotta G, Anders HJ, Schulz C, Schraml BU. 2020. The kidney contains ontogenetically distinct dendritic cell and macrophage subtypes throughout development that differ in their inflammatory properties. Journal of the American Society for Nephrology .31(2), 257-78.

Papaioannou NE, Pasztoi M, Schraml BU*. 2019. Understanding the Functional Properties of Neonatal Dendritic Cells: A Doorway to Enhance Vaccine Effectiveness? Frontiers in Immunology, 9: 553–8    

Schraml BU, van Blijswijk J, Zelenay S, Whitney PG, Filby A, Acton SE, Rogers NC, Moncaut N, Carvajal JJ, Reis e Sousa C. 2013. Genetic tracing via expression history of DNGR-1 defines dendritic cells as a hematopoietic lineage. Cell. 154(4):843-858.