Quantitative proteomics of natural dendritic cell subsets

Abstract

Dendritic cells (DCs) are a critical bridge between innate and adaptive immunity. They are a heterogeneous population composed of various subsets that modulate different aspects of the immune response. It is now clear that immunometabolism underpins all aspects of DC biology, from development to maturation and disease response. However, detailed characterisation of the metabolic phenotypes that dictate natural DC function is still in its infancy. The goal of immunometabolism research is to translate basic metabolic findings to generate novel therapeutic approaches in the treatment of infection and disease. As DCs orchestrate both innate and adaptive responses, striking the balance between tolerance and inflammation, they are prime candidates for immunotherapeutic interventions.

In recent years, quantitative proteomics has emerged as a powerful technique to investigate immune cell metabolism and function. The ability to simultaneously characterise the expression of thousands of proteins allows detailed mechanistic analysis of the metabolic machinery, revealing novel metabolic regulators of immune function. This project applies quantitative proteomics to study the immunometabolic features of natural type-1 conventional dendritic cells (cDC1), type-2 conventional dendritic cells (cDC2) and plasmacytoid dendritic cells (pDC). This approach reveals substantial metabolic heterogeneity between cDC1s and cDC2s. In particular, it was revealed that the differential activity of the amino acid transporter, SLC7A5, controls antigen processing and presentation by modulating the activity of the kinase mechanistic target of rapamycin complex 1 (mTORC1). Finally, this project identifies that pDCs have conserved enrichment of the iron transporter, the transferrin receptor (Tfrc). However, in silico and functional analysis of iron utilisation by pDCs indicates an iron-independent role of Tfrc.

Overall, the data presented in this thesis contribute to the field by providing mechanistic insight into the metabolic processes that underpin natural DC biology and identifying, as of yet, undescribed regulators of DC function.