The role of Complement and MHC in innate and adaptive immunity cooperation

Abstract

Major histocompatibility complex class II (MHC II) molecules are expressed by antigen presenting cells and essential for the development and activation of CD4+ T cells. Complement component 3 (C3) is the central component of the complement system and its activation is known to induce protective functions as part of the innate immune system. In this study, we have identified the unknown cooperation of these two central molecules of the adaptive and innate immune system, by describing their covalent association on the surface of conventional dendritic cells (cDCs). This in turn led to their ablation and enriched trogocytosis by marginal zone (MZ) B cells. We therefore describe two novel instances of intersection between the innate and adaptive immune systems, one at the molecular and the other at the cellular level, namely the covalent binding of activated C3 to MHC II and the cellular interaction between cDCs and MZ B cells based on a novel molecular communication axis.

Chapter 3 investigates the biochemical mechanisms of MARCHF1-mediated C3 deposition in cDCs and describes the binding of activated C3 to surface MHC II molecules in scenarios where its surface expression is enriched due to impaired ubiquitination. Biochemical analyses revealed the covalent association of C3dg and C3d, the two smallest C3 fragments, specifically to the N-linked carbohydrate of MHC IIalpha. This novel function of surface MHC II molecules as an acceptor for the covalent association of complement C3 was cDC-specific and also observed in human cDCs from blood samples. In Chapter 4 we explore the physiological role/consequence of enriched MHC II-dependent C3 fixation on cDCs and identified the specific and significant loss of splenic cDCs, associated with enriched C3 deposition. Furthermore, we identified the appearance of cDC-specific markers at the surface of MZ B cells that lacked the transcriptional expression for these proteins, also associated with enriched C3 deposition. Chapter 5 demonstrates C3-mediated trogocytosis of cDCs by MZ B cells, in which the latter acquire membrane fractions, as well as surface proteins and peptide-loaded MHC II molecules from cDCs. Importantly this intercellular exchange of membrane proteins was unidirectional and dependent on complement receptor 2 (CR2) expression in B cells, which indicates that C3-mediated trogocytosis is a coordinated cellular process.

In summary, this thesis provides comprehensive analyses on the interplay of innate and adaptive immunity, both on a molecular and cellular level. The data presented in this thesis indicate fundamental new roles for both MHC II and C3, in which surface MHC II serves as an acceptor for covalent C3 binding, which in turn is a driving mediator for close cell-cell interactions between cDCs and MZ B cells and unidirectional trogocytosis.