1 PhD project offered in the IPP winter call Molecular Biomedicine & Ageing

Scientific Background

Type 2 immune responses play an important role in the defense against parasites, effective wound healing and protection against toxins. Type 2 immune responses have however also been associated with detrimental immunity such as allergy, the suppression of proinflammatory immunity and the reprogramming of proinflammatory monocytes and macrophages. Type 2 associated immunity has also been described within the tumor microenvironment of solid tumors, leading to ineffective tumor killing.

While the mechanisms that drive type 2 associated immune responses in solid tumors are still unclear, our preliminary data show that a unique subset of dermal dendritic cells becomes highly activated in models of allergy and anti-parasite type 2 immunity. These Dendritic cells have been linked to the priming of Th2 cells and are also highly activated by S. aureus antigens and present in solid tumors. 

We therefore hypothesize that these Dendritic cells play an important role in driving type 2 associated immune diversion in the context of skin tumors and opportunistic bacterial skin infection.

PhD project: The role of dermal Dendritic cells in immune diversion of skin infection and skin tumors

Within this project we have three sub-aims:

Aim 1: Identify the molecular profile of different populations of dermal dendritic cells and define their unique characteristics in driving type 2 immune responses
Aim 2: Define the role of dermal dendritic cells in S. aureus infection
Aim 3: Identify immune diversion mechanisms induced by dermal dendritic cells in skin tumors 

This entire project focuses on studies in murine models, as the complex immune interactions analyzed here cannot be studied in vitro and human material from skin infections is not readily available. This projects aims to identify a skin specific immunological mechanism and assess its involvement skin infection and skin tumors.

In Aim 1 you will become an expert in high-dimensional flow cytometry and how to identify different Dendritic Cell subsets in the murine skin and compare those profiles to other tissues. RNA-seq and confocal microscopy will help you define unique molecular signatures and developmental pathways that determine the fate and function of those subsets. With this knowledge you will define their unique characteristics in driving type 2 immune responses using in vivo and in vitro approaches, including allergic reactions, TLR agonists, bacterial and parasite products and tumor cell antigens.

Having determined the unique functionality in dermal DC in type 2 immunity you will investigate their role in promoting opportunistic S. aureus infections (Aim 2) and tumor growth (Aim 3) in in vivo models and use transgenic mice to deplete specific DC subsets at different timepoints.

Studying the dominant T cell responses and clinical outcomes of infection and tumor growth that develop in the presence and absence of dermal DC will help you determine how skin immune responses are diverted in the context of opportunistic bacterial infections and skin cancer and identify novel treatment approaches.

If you are interested in this project, please select Mayer (SkinDC) as your project preference in the IPP application platform.

Publications relevant to this project

Mayer JU, Hilligan KL, Chandler JS, Eccles DA, Old SI, Domingues RG, Yang J, Webb GR, Munoz-Erazo L, Hyde EJ, Wakelin KA, Tang SC, Chappell SC, von Daake S, Brombacher F, Mackay CR, Sher A, Tussiwand R, Connor LM, Ortega DG, Jankovic D, Gros GL, Hepworth MR, Lamiable O, Ronchese F (2021) Homeostatic IL-13 in healthy skin directs dendritic cell differentiation to promote TH2 and inhibit TH17 cell polarization. Nat. Immunol., 1 (13). Link

Bosteels C, Neyt K, Vanheerswynghels M, van Helden MJ, Sichien D, Debeuf N, De Prijck S, Bosteels V, Vandamme N, Martens L, Saeys Y, Louagie E, Lesage M, Williams DL, Tang SC, Mayer JU, Ronchese F, Scott CL, Hammad H, Guilliams M, Lambrecht BN. (2020) Inflammatory Type 2 CDCs Acquire Features of CDC1s and Macrophages to Orchestrate Immunity to Respiratory Virus Infection. Immunity, 52 (6), 1039-1056 e9. Link

Kumamoto Y, Linehan M, Weinstein JS, Laidlaw BJ, Craft JE, Iwasaki A (2013) CD301b+ dermal dendritic cells drive T helper 2 cell-mediated immunity. Immunity. Mar;39(4):733–43. Link

Cook PC, Brown SL, Houlder EL, Baker S, Svedberg FR, Howell G, Bertuzzi M, Boon L, Konkel JE, Allen JE, MacDonald AS (2023) Mgl2+ cDC2s coordinate fungal allergic airway type 2, but not type 17, inflammation.bioRxiv; p. 2023.11.24.568263. Link