The immunoglobulin A (IgA) is produced to defend mucosal surfaces from environmental organisms, but host defenses against the very heavy load of intestinal commensal microorganisms are poorly understood. The IgA against intestinal commensal bacterial antigens was analyzed; it was not simply "natural antibody" but was specifically induced and responded to antigenic changes within an established gut flora. In contrast to IgA responses against exotoxins, a significant proportion of this specific anti-commensal IgA induction was through a pathway that was independent of T cell help and of follicular lymphoid tissue organization, which may reflect an evolutionarily primitive form of specific immune defense.

Summary Effective humoral immunity depends on the support of B cell responses by T-follicular helper (Tfh) cells. Whilst it has been proposed that Tfh cell differentiation requires T-B interactions, the relative contribution of specific populations of Ag presenting cells remains unknown. We employed three independent strategies that compromised interactions between CD4+ T cells and activated B cells in vivo. Whereas the expansion of CD4+ T cells was relatively unaffected, Tfh cell differentiation was completely blocked in all scenarios. Surprisingly, augmenting antigen presentation by non-B cells rescued Tfh cell differentiation, as determined by surface phenotype, gene expression and germinal center localization. We conclude that although Ag presentation by responding B cells is typically required for the generation of Tfh cells, this does not result from the provision of a unique B cell-derived signal, but rather because responding B cells rapidly become the primary source of antigen.

Humoral immunity depends on both rapid and long-term antibody production against invading pathogens. This is achieved by the generation of spatially distinct extrafollicular plasmablast and follicular germinal center (GC) B cell populations, but the signals that guide responding B cells to these alternative compartments have not been fully elucidated. Here, we show that expression of the orphan G protein-coupled receptor Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) by activated B cells was essential for their movement to extrafollicular sites and induction of early plasmablast responses. Conversely, downregulation of EBI2 enabled B cells to access the center of follicles and promoted efficient GC formation. EBI2 therefore provides a previously uncharacterized dimension to B cell migration that is crucial for coordinating rapid versus long-term antibody responses.

T cell activation by APCs is positively and negatively regulated by members of the B7 family. We have identified a previously unknown function for B7 family-related protein V-set and Ig domain-containing 4 (VSIG4). In vitro experiments using VSIG4-Ig fusion molecules showed that VSIG4 is a strong negative regulator of murine and human T cell proliferation and IL-2 production. Administration to mice of soluble VSIG4-Ig fusion molecules reduced the induction of T cell responses in vivo and inhibited the production of Th cell-dependent IgG responses. Unlike that of B7 family members, surface expression of VSIG4 was restricted to resting tissue macrophages and absent upon activation by LPS or in autoimmune inflammatory foci. The specific expression of VSIG4 on resting macrophages in tissue suggests that this inhibitory ligand may be important for the maintenance of T cell unresponsiveness in healthy tissues. IntroductionT cell responses are regulated by a complex network of activating and inhibitory signals. Recognition of peptides presented by MHC molecules is usually not sufficient for full T cell activation, but additional signals from costimulatory molecules are required (1-4). The most prominent costimulatory molecule expressed on T cells is CD28, interacting with the B7 family members CD80 and CD86 (5, 6). Engagement of CD28 facilitates T cell activation by enhancing TCR-mediated signaling and reducing the number of TCRs that need to be engaged for activation (7,8). CTLA-4, a close homolog of CD28, also engages CD80 and CD86 (5, 6). Yet it serves a completely different function, since it reduces rather than enhances T cell responses.Novel members of the CD28/B7 families have been identified recently. ICOS, engaging ICOSL (9, 10), has a function homologous to that of CD28 and generally enhances T cell responses; under some conditions, ICOS stimulation appears to selectively favor induction of Th2 cells (11,12). Moreover, ICOS has been shown to mediate CD28-independent antiviral responses (13,14) and to enhance antibody responses and germinal center formation (15, 16). Another new member of the family is the inhibitory receptor programmed death 1 (PD-1), which interacts with PD-ligand 1 (PD-L1) (B7-H1) and PD-L2 (B7-DC) (17-21). PD-1 has a function similar to that of CTLA-4 and downmodulates T cell responses (18,19). The same is true for BTLA, a CD28 homolog interacting with herpesvirus entry mediator on APCs (22, 23). There are 2 more B7 homologs with unknown receptors on T cells, called B7-H3 (24) and B7-H4 (B7x, B7S1) (22,25,26). Their function is less well established. B7-H3 is upregulated upon inflammation and has been suggested to function as both a positive and negative regulator of T cell responses (27, 28). B7-H4 is also expressed on DCs upon activation and is thought to function as a negative regulator (25).Here we report the identification of a novel function of V-set and Ig domain-containing 4 (VSIG4). In vitro experiments showed that VSIG4 is at least as potent at inhibiting T cell responses as PD-L...