The combination of ISCOMATRIX adjuvant and TLR agonists induces regression of established solid tumors in vivo.

The development of therapeutic vaccines for treatment of established cancer has proven challenging. Cancer vaccines not only need to induce a robust tumor Ag-specific immune response but also need to overcome the tolerogenic and immunosuppressive microenvironments that exist within many solid cancers. ISCOMATRIX adjuvant (ISCOMATRIX) is able to induce both tumor Ag-specific cellular and Ab responses to protect mice against tumor challenge, but this is insufficient to result in regression of established solid tumors.

Combination of adjuvants: the future of vaccine design.

It is thought that the development of vaccines for the treatment of infectious diseases and cancer is likely to be achieved in the coming decades. This is partially due to a better understanding of the regulatory networks connecting innate with adaptive immune responses. The innate immune response is triggered by the recognition of conserved pathogen-associated molecular patterns by germ line-coded pattern recognition receptors.

Id2-mediated inhibition of E2A represses memory CD8+ T cell differentiation.

The transcription factor inhibitor of DNA binding (Id)2 modulates T cell fate decisions, but the molecular mechanism underpinning this regulation is unclear. In this study we show that loss of Id2 cripples effector differentiation and instead programs CD8(+) T cells to adopt a memory fate with increased Eomesodermin and Tcf7 expression. We demonstrate that Id2 restrains CD8(+) T cell memory differentiation by inhibiting E2A-mediated direct activation of Tcf7 and that Id2 expression level mirrors T cell memory recall capacity.

B and T cells collaborate in antiviral responses via IL-6, IL-21, and transcriptional activator and coactivator, Oct2 and OBF-1.

A strong humoral response to infection requires the collaboration of several hematopoietic cell types that communicate via antigen presentation, surface coreceptors and their ligands, and secreted factors. The proinflammatory cytokine IL-6 has been shown to promote the differentiation of activated CD4(+) T cells into T follicular helper cells (T(FH) cells) during an immune response. T(FH) cells collaborate with B cells in the formation of germinal centers (GCs) during T cell-dependent antibody responses, in part through secretion of critical cytokines such as IL-21.

Id2 expression delineates differential checkpoints in the genetic program of CD8α+ and CD103+ dendritic cell lineages.

Dendritic cells (DCs) have critical roles in the induction of the adaptive immune response. The transcription factors Id2, Batf3 and Irf-8 are required for many aspects of murine DC differentiation including development of CD8α(+) and CD103(+) DCs. How they regulate DC subset specification is not completely understood.

Bid and Bim collaborate during induction of T cell death in persistent infection.

Upon Ag encounter, naive T cells undergo extensive Ag-driven proliferation and can differentiate into effector cells. Up to 95% of these cells die leaving a small residual population of T cells that provide protective memory. In this study, we investigated the contribution of the BH3-only family protein Bid in the shutdown of T cell responses after acute and persistent infection.

Interference with dendritic cell populations limits early antigen presentation in chronic γ-herpesvirus-68 infection.

A critical factor influencing the ability of the host to mount a robust immune response against a virus depends on the rapid recruitment of dendritic cells (DCs) presenting Ags. From the outset, this step sets the tempo for subsequent activation of virus-specific T cells. Despite this, how induction of the immune response might be modified by pathogens with the capacity to establish persistence is unclear.

Mouse models of viral infection: influenza infection in the lung.

Respiratory viral infections are a major cause of morbidity and mortality. Protection of the respiratory tract from pathogen infections, such as influenza virus, requires the orchestrated activation and trafficking of pulmonary dendritic cells (DCs) from the lung to the lymph node (LN) in order to ensure optimized T-cell responses. Gaining a better understanding of the cellular and molecular processes that protect the lung during infection is essential for future advances in vaccine strategies and treatments.

Selected Toll-like receptor ligands and viruses promote helper-independent cytotoxic T cell priming by upregulating CD40L on dendritic cells.

CD40L (CD154) on CD4(+) T cells has been shown to license dendritic cells (DCs) via CD40 to prime cytotoxic T lymphocyte (CTL) responses. We found that the converse (CD40L on DCs) was also important. Anti-CD40L treatment decreased endogenous CTL responses to both ovalbumin and influenza infection even in the absence of CD4(+) T cells.

Dendritic cells in viral infections.

Antigen presenting cells (APCs) are recognized as key initiators of adaptive immunity, particularly to pathogens, by eliciting a rapid and potent immune attack on infected cells. Amongst APCs, dendritic cells (DCs) are specially equipped to initiate and regulate immune responses in a manner that depends on signals they receive from microbes and their cellular environment. To achieve this, they are equipped with highly efficient mechanisms that allow them to detect pathogens, to capture, process and present antigens, and to activate and guide the differentiation of T cells into effector and memory cells.

Differential MHC class II synthesis and ubiquitination confers distinct antigen-presenting properties on conventional and plasmacytoid dendritic cells.

The importance of conventional dendritic cells (cDCs) in the processing and presentation of antigen is well established, but the contribution of plasmacytoid dendritic cells (pDCs) to these processes, and hence to T cell immunity, remains unclear. Here we showed that unlike cDCs, pDCs continued to synthesize major histocompatibility complex (MHC) class II molecules and the MHC class II ubiquitin ligase MARCH1 long after activation. Sustained MHC class II-peptide complex formation, ubiquitination and turnover rendered pDCs inefficient in the presentation of exogenous antigens but enabled pDCs to continuously present endogenous viral antigens in their activated state.

Dendritic cells: driving the differentiation programme of T cells in viral infections.

Protective immunity against viral pathogens depends on the generation and maintenance of a small population of memory CD8(+) T cells. Successful memory cell generation begins with early interactions between naïve T cell and dendritic cells (DCs) within the inflammatory milieu of the secondary lymphoid tissues. Recent insights into the role of different populations of DCs, and kinetics of antigen presentation, during viral infections have helped to understand how DCs can shape the immune response.

Multiple dendritic cell populations activate CD4+ T cells after viral stimulation.

Dendritic cells (DC) are a heterogeneous cell population that bridge the innate and adaptive immune systems. CD8alpha DC play a prominent, and sometimes exclusive, role in driving amplification of CD8(+) T cells during a viral infection. Whether this reliance on a single subset of DC also applies for CD4(+) T cell activation is unknown.

Dendritic cells present lytic antigens and maintain function throughout persistent gamma-herpesvirus infection.

The activation and maintenance of Ag-specific CD8(+) T cells is central to the long-term control of persistent infections. These killer T cells act to continuously scan and remove reservoirs of pathogen that have eluded the acute immune response. Acutely cleared viral infections depend almost exclusively on dendritic cells (DC) to present Ags to, and to activate, the CD8(+) T cell response.

Dendritic cell preactivation impairs MHC class II presentation of vaccines and endogenous viral antigens.

When dendritic cells (DCs) encounter signals associated with infection or inflammation, they become activated and undergo maturation. Mature DCs are very efficient at presenting antigens captured in association with their activating signal but fail to present subsequently encountered antigens, at least in vitro. Such impairment of MHC class II (MHC II) antigen presentation has generally been thought to be a consequence of down-regulation of endocytosis, so it might be expected that antigens synthesized by the DCs themselves (for instance, viral antigens) would still be presented by mature DCs.

CD4+ T cells specific for a model latency-associated antigen fail to control a gammaherpesvirus in vivo.

CD4(+) T cells play a major role in containing herpesvirus infections. However, their cellular targets remain poorly defined. In vitro CD4(+) T cells have been reported to kill B cells that harbor a latent gammaherpesvirus.

Systemic activation of dendritic cells by Toll-like receptor ligands or malaria infection impairs cross-presentation and antiviral immunity.

The mechanisms responsible for the immunosuppression associated with sepsis or some chronic blood infections remain poorly understood. Here we show that infection with a malaria parasite (Plasmodium berghei) or simple systemic exposure to bacterial or viral Toll-like receptor ligands inhibited cross-priming. Reduced cross-priming was a consequence of downregulation of cross-presentation by activated dendritic cells due to systemic activation that did not otherwise globally inhibit T cell proliferation.

Bone marrow-derived cells expand memory CD8+ T cells in response to viral infections of the lung and skin.

While naive CD8(+) T cells have been shown to require bone marrow-derived dendritic cells (DC) to initiate immunity, such a requirement for memory CD8(+) T cells has had limited assessment. By generating bone marrow chimeras that express the appropriate antigen-presenting molecules on either radiation-sensitive bone marrow-derived or radiation-resistant non-bone marrow-derived compartments, we showed that both primary and secondary immune responses to influenza virus infection of the lung were initiated in the draining LN. This required cells of bone marrow origin, most likely DC, for optimal expansion within the secondary lymphoid compartment.

Impairment of humoral immunity to Plasmodium falciparum malaria in pregnancy by HIV infection.

Background: HIV infection increases the risk of malaria infection in pregnant women. Antibodies to variant surface antigens (VSA) on infected erythrocytes might protect against malaria in pregnancy. We postulated that HIV-induced impairment of humoral immunity to VSA mediates the increased susceptibility to malaria.