Complement-dependent transport of antigen into B cell follicles

Abstract

Since the original proposal by Fearon and Locksley (Fearon and Locksley. 1996. Science 272: 50-53) that the complement system linked innate and adaptive immunity, there has been a rapid expansion of studies on this topic. With the advance of intravital imaging, a number of recent papers revealed an additional novel pathway in which complement C3 and its receptors enhance humoral immunity through delivery of Ag to the B cell compartment. In this review, we discuss this pathway and highlight several novel exceptions recently found with a model influenza vaccine, such as mannose-binding lectin opsonization of influenza and uptake by macrophages, and the capture of virus by dendritic cells residing in the medullary compartment of peripheral lymph nodes.

Figure 1

The conduit network, formed by collagen fibers, is secreted by the fibroblastic reticular cells (FRC) and drains small antigens from the subcapsular sinus (SCS) area of the lymph node to the B cell follicle. Follicular dendritic cells (FDC) present in the follicle are closely associated with the collagen fibers. MΦ; indicates subcapsular sinus macrophages. Arrows indicate conduit opening into the sinus in electron micrograph on right panel. EM is from S. Gonzalez, unpublished.

Figure 2

(a) Pathways for the circulation of antigen (Ag) in the LN. (1) Complement C3 opsonizes antigen in presence of antibody. C3-coated Immune complexes (C3-IC) are formed by the deposition of complement proteins and IgG on the surface of the antigen. (2) The retention of C3-IC on the surface of the subcapsular sinus macrophages (SSM) is CR3 and FcRIIb dependent. (3) B cells transport C3-IC from the surface of the SSM to the FDC in a CD21 dependent manner. (4) C3-IC are transferred to FDC. (5) Cognate B cells acquire small Ag drained via FRC-conduits directly or from FDC surface. (b) Influenza virus uptake by SSM is MBL dependent.

Figure 3

Recognition of C3-tagged antigen via CD21 and CD35 enhances B cell differentiation at three major stages. Complement receptors CD21 and CD35 play an important role in at least three stages of B cell differentiation. Stage 1: co-ligation of C3d-antigen with BCR lowers threshold of B cell activation leading to migration of the activated B cell to the T cell:B cell boundary where cognate interaction occurs and B cells receive co-stimulation via CD40. Stage 2: activated B cells enter a germinal center where they begin further differentiation including rapid cell division, somatic cell hypermutation (SHM) and class switch recombination (CSR). Stage 3: following clonal selection (binding of antigen on FDC) the GC B cell differentiates into an effector cell (plasma cell) or memory B cell. Maintenance of B effector and memory cells is dependent on presence of antigen on FDC.

Figure 4

Lymph-borne UV-inactive influenza (strainPR8) fills the subcapsular (SCS) of the LN, where it is partially taken up by SSM. Binding of virus to SSM is MBL-dependent. Virions are channeled to the LN medulla where medullary macrophages (MM) and resident dendritic cells (DC) capture them in a SIGN-R1-dependent manner. Model speculates that C1q is activated by SIGN-R1 leading to C3 activation and deposition on PR8. Subsequently, resident DC transport C3-coated virus complex to the follicles where it is transferred to FDC.