Follicular dendritic cells: dynamic antigen libraries.

Follicular dendritic cells (FDCs) are essential for high-affinity antibody production and for the development of B cell memory. Historically, FDCs have been characterized as 'accessory' cells that passively support germinal centre (GC) responses. However, recent observations suggest that FDCs actively shape humoral immunity. In this Review, we discuss recent findings concerning the antigen acquisition and retention functions of FDCs, and relevant implications for protective immunity. Furthermore, we describe the roles of FDCs within GCs in secondary lymphoid organs and discuss FDC development within this dynamic environment. Finally, we discuss how a better understanding of FDCs could facilitate the design of next-generation vaccines.

STAT4-dependent and -independent Th2 responses correlate with protective immunity against lung infection with Pneumocystis murina.

Although it is clear that the loss of CD4(+) T cells is a predisposing factor for the development of Pneumocystis pneumonia, specific Th mechanisms mediating protection are not well understood. Th1, Th2, and Th17 responses have each been implicated in protective responses during infection. As STAT4 may promote Th1 and Th17 development, yet antagonize Th2 development, we investigated its role in Pneumocystis murina host defense. STAT4 was required for Th1 and, unexpectedly, Th2 responses in the lungs of C57BL/6 (BL/6) and BALB/c mice 14 d postchallenge, but only BALB/c Stat4(-/-) mice demonstrated susceptibility to P. murina lung infection. BL/6 Stat4(-/-), but not BALB/c Stat4(-/-), mice maintained an enhanced alternatively activated (M2) macrophage signature in the lungs, which we have previously reported to be associated with enhanced P. murina clearance. In addition, anti-P. murina class-switched Abs were increased in BL/6 Stat4(-/-) mice, but not BALB/c Stat4(-/-) mice. Supporting our experimental observations, plasma from HIV-infected individuals colonized with Pneumocystis jirovecii contained significantly lower levels of the Th2 cytokines IL-4, IL-5, and IL-13 compared with HIV-infected individuals who were not colonized. Collectively, our data suggest that robust local and systemic Th2-mediated responses are critical for immunity to Pneumocystis.

Lymphotoxin α1ß2 expression on B cells is required for follicular dendritic cell activation during the germinal center response.

CD19-deficient mice were used as a model to study follicular dendritic cell (FDC) activation because these mice have normal numbers of FDC-containing primary follicles, but lack the ability to activate FDCs or form GCs. It was hypothesized that CD19 expression is necessary for B-cell activation and upregulation of membrane lymphotoxin (mLT) expression, which promotes FDC activation. Using VCAM-1 and FcγRII/III as FDC activation markers, it was determined that the adoptive transfer of CD19(+) wild-type B cells into CD19-deficient hosts rescued GC formation and FDC activation, demonstrating that CD19 expression on B cells is required for FDC activation. In contrast, CD19(+) donor B cells lacking mLT were unable to induce VCAM-1 expression on FDCs, furthermore FcγRII/III upregulation was impaired in FDCs stimulated with mLT-deficient B cells. VCAM-1 expression on FDCs, but not FcγRII/III, was rescued when CD19-deficient B cells expressing transgenic mLT were cotransferred into recipient mice with CD19(+) , mLT-deficient B cells, suggesting that FDC activation requires the CD19-dependent upregulation of mLT on activated B cells. Collectively, these data demonstrate that activated B cells are responsible for the initiation of FDC activation resulting in a microenvironment supportive of GC development and maintenance.

Marginal zone B cells regulate antigen capture by marginal zone macrophages.

The marginal zone (MZ) of the mouse spleen contains macrophages that express receptors that trap pathogens, including the scavenger receptor macrophage receptor with a collagenous structure and the C-type lectin specific intracellular adhesion molecule-grabbing nonintegrin receptor 1 (SIGN-R1). We previously reported that expression of SIGN-R1 was decreased in CD19-deficient mice. In this study, we demonstrate that SIGN-R1 is expressed on a subset of macrophage receptor with a collagenous structure (MARCO)(+) macrophages. This subset is diminished when MZ B cells are absent due to either genetic developmental defects or following transient migration of B cells out of the MZ. When B cells return to the MZ, there is a delay in recovery of SIGN-R1-expressing macrophages. During this period, capture of Ficoll, which for the macrophages requires SIGN-R1, remains defective not only by the macrophages, but also by the B cells. Thus, MZ B cells regulate expression of molecules on macrophages that are important for trapping Ag, which, in turn, is required for Ag capture by the B cells.