Follicular helper T (TFH) cells are the class of effector TH cells that regulates the stepwise development of antigen-specific B cell immunity in vivo. Deployment of CXCR5+ TFH cells to B cell zones of lymphoid tissues and stable cognate interactions with B cells are central to the delivery of antigen-specific TFH function. Recent advances help to unravel distinctive elements of developmental programming for TFH cells and unique effector TFH functions focused on antigen-primed B cells. Understanding the regulatory functions of TFH cells in the germinal center and the subsequent regulation of memory B cell responses to antigen recall represent the frontiers of this research area with the potential to alter fundamentally the design of future vaccines.

SUMMARY Follicular helper T (TFH) cells are a class of helper T cells specialized in the cognate control of antigen-specific B cell immunity. Upon first contact with antigen-primed B cells, pre-germinal center effector TFH cells promote B cell clonal expansion, antibody isotype switch, plasma cell differentiation and the induction of germinal centers. In contrast, within germinal centers, TFH cells regulate the fate of antigen-specific GC B cells expressing high-affinity variant B cell receptors to promote memory B cell and long-lived plasma cell development. Recent studies unravel multiple signals controlling TFH development and functional sub-types of antigen-specific TFH cells, including memory TFH cells that accelerate memory B cell responses to antigen re-challenge in vivo.

How T cell receptor (TCR) specificity evolves in vivo after protein vaccination is central to the development of helper T (Th) cell function. Most models of clonal selection in the Th cell compartment favor TCR affinity-based thresholds. Here, we demonstrated that depot-forming vaccine adjuvants did not require Toll-like receptor (TLR) agonists to induce clonal dominance in antigen-specific Th cell responses. However, readily dispersible adjuvants using TLR-9 and TLR-4 agonists skewed TCR repertoire usage by increasing TCR selection thresholds and enhancing antigen-specific clonal expansion. In this manner, vaccine adjuvants control the local accumulation of Th cells expressing TCR with the highest peptide MHC class II binding. Clonal composition was altered by mechanisms that blocked the local propagation of clonotypes independently of antigen dose and not as a consequence of interclonal competition. This capacity of adjuvants to modify antigen-specific Th cell clonal composition has fundamental implications for the design of future protein subunit vaccines.

Kaposi's sarcoma-associated herpesvirus (KSHV) is closely associated with Kaposi's sarcoma and certain B-cell lymphomas. The fourth open reading frame of the KSHV genome encodes a protein (KSHV complement control protein (KCP, previously termed ORF4)) predicted to have complement-regulating activity. Here, we show that soluble KCP strongly enhanced the decay of classical C3-convertase but not the alternative pathway C3-convertase, when compared with the host complement regulators: factor H, C4b-binding protein, and decay-accelerating factor. The equilibrium affinity constant (K D ) of KCP for C3b and C4b was determined by surface plasmon resonance analysis to range between 0.47-10 M and 0.025-6.1 M, respectively, depending on NaCl concentration and cation presence. Soluble and cell-associated KCP acted as a cofactor for factor I (FI)-mediated cleavage of both C4b and C3b and induced the cleavage products C4d and iC3b, respectively. In the presence of KCP, FI further cleaved iC3b to C3d, which has never been described before as complement receptor 1 only mediates the production of C3dg by FI. KCP would enhance virus pathogenesis through evading complement attack, opsonization, and anaphylaxis but may also aid in targeting KSHV to one of its host reservoirs since C3d is a ligand for complement receptor 2 on B-cells.Kaposi's sarcoma-associated herpesvirus (KSHV) 1 is the likely etiologic agent of Kaposi's sarcoma and is the most recently identified member of the human Herpesviridae family (1, 2). KSHV is also associated with the B-cell tumors body cavitybased primary effusion lymphomas and the plasma cell variant of multicentric Castleman's Disease (for reviews, see Refs. 3 and 4). KSHV belongs to the rhadinovirus genus of the Gammaherpesvirinae subfamily, the prototype of which is Herpesvirus saimiri (HVS). The long unique region of the KSHV genome comprises 140.5 kb and contains over 80 open reading frames (ORFs) (5). Several of the ORFs encode host cell homologues (e.g. viral cyclin D, viral interleukin-8 G protein-coupled receptor, and a bcl-2 homologue) with the potential to regulate the cell cycle and the immune response thereby contributing to the virulence and the pathogenesis of KSHV (5,6).The fourth open reading frame, ORF4, was initially speculated to have complement regulatory abilities based on its homology to human complement regulators decay-accelerating factor (DAF) and membrane cofactor and to previously described virus-encoded complement inhibitors (5). The KSHV ORF4 gene is predicted to encode a KCP protein of 550 amino acids (data base reference SPTREMBL:O40912), and the first 280 amino acids are predicted to encode four complement control protein (CCP) domains. CCP domains are defined by a consensus sequence of ϳ60 amino acids containing four invariant cysteine residues that form disulfide links, which results in the CCP forming a globular domain with a hydrophobic core enclosed by ␤-strands (7,8). While the CCP domain is not exclusive to complement control proteins, all but one of the C3-co...

Complement, which bridges innate and adaptive immune responses as well as humoral and cell-mediated immunity, is antiviral. Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a lytic cycle protein called KSHV complement control protein (KCP) that inhibits activation of the complement cascade. It does so by regulating C3 convertases, accelerating their decay, and acting as a cofactor for factor I degradation of C4b and C3b, two components of the C3 and C5 convertases. These complement regulatory activities require the short consensus repeat (SCR) motifs, of which KCP has four (SCRs 1 to 4). We found that in addition to KCP being expressed on the surfaces of experimentally infected endothelial cells, it is associated with the envelope of purified KSHV virions, potentially protecting them from complement-mediated immunity. Furthermore, recombinant KCP binds heparin, an analogue of the known KSHV cell attachment receptor heparan sulfate, facilitating infection. Treating virus with an anti-KCP monoclonal antibody (MAb), BSF8, inhibited KSHV infection of cells by 35%. Epitope mapping of MAb BSF8 revealed that it binds within SCR domains 1 and 2, also the region of the protein involved in heparin binding. This MAb strongly inhibited classical C3 convertase decay acceleration by KCP and cofactor activity for C4b cleavage but not C3b cleavage. Our data suggest similar topological requirements for cell binding by KSHV, heparin binding, and regulation of C4b-containing C3 convertases but not for factor I-mediated cleavage of C3b. Importantly, they suggest KCP confers at least two functions on the virion: cell binding with concomitant infection and immune evasion.