Marginal zone B cells acquire dendritic cell functions by trogocytosis

Marginal zone (MZ) B cells produce broad-spectrum antibodies that protect against infection early in life. In some instances, antibody production requires MZ B cells to display pathogen antigens bound to major histocompatibility complex class II (MHC II) molecules to T cells. We describe the trogocytic acquisition of these molecules from conventional dendritic cells (cDCs). Complement component 3 (C3) binds to murine and human MHC II on cDCs. MZ B cells recognize C3 with complement receptor 2 (CR2) and trogocytose the MHC II–C3 complexes, which become exposed on their cell surface. The ubiquitin ligase MARCH1 limits the number of MHC II–C3 complexes displayed on cDCs to prevent their elimination through excessive trogocytosis. Capture of C3 by MHC II thus enables the transfer of cDC-like properties to MZ B cells. Description MZ B cells take on “a-gnaw-ther” role Marginal zone (MZ) B cells are a subset of lymphoid tissue–resident B cells specializing in the rapid production of polyreactive immunoglobulin M antibodies. Schriek et al. found that MZ B cells can also emulate conventional dendritic cells (cDCs), which present antigens to T cells. Complement receptor 2 (CR2) expressed by MZ B cells recognizes complement component 3 (C3) bound to peptide-loaded major histocompatibility complex class II molecules (pMHC II) on the surface of cDCs. MZ B cells can then “nibble” pMHCII–C3 complexes from cDCs and display them on their own membranes in a process called trogocytosis. A ubiquitin ligase, MARCH1, limits the damage to cDCs by regulating the levels of pMHCII–C3 complexes expressed on the surface of cDCs. —STS Marginal zone B cells trogocytose dendritic cell membranes, which enables them to present antigens to T cells. INTRODUCTION Effective immunity is multilayered, requiring the cooperation of various types of molecules and cells. Some types are components of the fast-responding innate arm of the immune system, like the molecules that constitute the complement system and marginal zone (MZ) B cells. Other types of molecules and cells participate in adaptive immune responses that provide long-term protection. These include conventional dendritic cells (cDCs) and major histocompatibility complex class II (MHC II) molecules. This study describes molecular linkages between complement and MHC II molecules that enable MZ B cells and cDCs to carry out cooperatively immunological functions that neither cell type can perform on its own. RATIONALE The initiation of adaptive immunity against infections requires cDCs to detect, capture, degrade, and present pathogen antigens. cDCs use their MHC II molecules to bind and display peptide fragments derived from these antigens. Recognition of the resulting pMHC II complexes by the antigen receptor of T cells elicits adaptive immune responses and, eventually, the establishment of protective immunological memory against the infectious agent. MZ B cells are specialized in the production of polyreactive antibodies that protect newborns and infants from different types of microorganisms. In some instances, MZ B cells require “help” from T cells to perform this function, which they obtain by displaying pMHC II complexes. This suggests that MZ B cells may be able to emulate the antigen-presenting activity of cDCs. RESULTS Complement component 3 (C3) is an abundant serum protein that constitutively adopts a reactive form in the absence of pathogens by a mechanism known as tickover. We determined that C3 binds to pMHC II exposed on the surface of mouse and human cDCs, forming a covalent bond with the carbohydrate moiety of the MHC II α chain. Because C3 can damage healthy cells, it is converted to inactive C3dg while still bound to pMHC II. These pMHC II–C3dg complexes are recognized by complement receptor 2 (CR2), which is highly expressed by MZ B cells. Interaction between CR2 and C3dg triggers the transfer of pMHC II–C3dg complexes, along with associated cDC membrane and additional proteins embedded in the membrane, from cDCs to MZ B cells—a process termed trogocytosis. The trogocytic MZ B cells are thus able to present pMHC II complexes to T cells they do not generate themselves but acquire from cDCs. Although trogocytosis is beneficial for MZ B cell function, it must be limited to prevent excessive damage and elimination of the trogocytosed cDCs. This takes place through an evolutionarily conserved mechanism, namely pMHC II–C3dg ubiquitination by a highly specialized ubiquitin ligase, MARCH1, embedded in the cDC plasma membrane. The ubiquitinated pMHC II–C3dg complexes are endocytosed and degraded intracellularly, reducing the number exposed on the cDC surface in the steady state. CONCLUSION Our results describe how C3 and MHC II interact and how this interaction enables MZ B cells and cDCs to cooperatively carry out functions they cannot perform individually. We demonstrate how an evolutionarily conserved mechanism for the constitutive elimination of potentially damaging C3 has been co-opted by cDCs to tag pMHC II complexes for capture by MZ B cells via trogocytosis. This mechanism expands the range of antigens that MZ B cells can present to T lymphocytes. The beneficial and deleterious consequences of trogocytosis are balanced by MARCH1 ubiquitination. Marginal zone B cells trogocytose dendritic cells, acquiring peptide-loaded MHC II molecules bound to complement C3 for antigen presentation to CD4+ T cells. Activated complement C3 binds MHC II on conventional dendritic cells (cDCs). The complexes are processed into MHC II–C3dg and either internalized via MARCH1-mediated ubiquitination or recognized by the complement receptor 2 (CR2) of marginal zone (MZ) B cells. The latter enables MZ B cells to trogocytose and display on their own membrane cDC receptors. Trogocytic MZ B cells expand their capacity to stimulate helper CD4+ T cells using antigen-loaded MHC II molecules generated by cDCs. Excessive trogocytosis eliminates cDCs, but MARCH1 prevents this by limiting the number of MHC II–C3dg complexes on cDCs.