Cross-reactivity and expansion of dengue-specific T cells during acute primary and secondary infections in humans.

Serotype-cross-reactive memory T cells responding to secondary dengue virus (DENV) infection are thought to contribute to disease. However, epitope-specific T cell responses have not been thoroughly compared between subjects with primary versus secondary DENV infection. We studied CD8(+) T cells specific for the HLA-A*1101-restricted NS3(133) epitope in a cohort of A11(+) DENV-infected patients throughout acute illness and convalescence. We compared the expansion, serotype-cross-reactivity, and activation of these cells in PBMC from patients experiencing primary or secondary infection and mild or severe disease by flow cytometry. Our results show expansion and activation of DENV-specific CD8(+) T cells during acute infection, which are predominantly serotype-cross-reactive regardless of DENV infection history. These data confirm marked T cell activation and serotype-cross-reactivity during the febrile phase of dengue; however, A11-NS3(133)-specific responses did not correlate with prior antigenic exposure or current disease severity.

Cross-reactive memory CD8(+) T cells alter the immune response to heterologous secondary dengue virus infections in mice in a sequence-specific manner.

Dengue virus is the causative agent of dengue fever and the more-severe dengue hemorrhagic fever (DHF). Human studies suggest that the increased risk of DHF during secondary infection is due to immunopathology partially mediated by cross-reactive memory T cells from the primary infection. To model T cell responses to sequential infections, we immunized mice with different sequences of dengue virus serotypes and measured the frequency of peptide-specific T cells after infection. The acute response after heterologous secondary infections was enhanced compared with the acute or memory response after primary infection. Also, the hierarchy of epitope-specific responses was influenced by the specific sequence of infection. Adoptive-transfer experiments showed that memory T cells responded preferentially to the secondary infection. These findings demonstrate that cross-reactive T cells from a primary infection alter the immune response during a heterologous secondary infection.

Uncovering the dark side of TNF.

In the early 1980s, in search of the cytokine that triggers disease- associated weight loss and lethal shock, Anthony Cerami and Bruce Beutler purified "cachectin." They soon found out that their malevolent cytokine already had another name-tumor necrosis factor (TNF)-and was being lauded as a potential antitumor agent.

Ralph Steinman: dendritic cells bring home the Lasker.

Ralph Steinman is perhaps best known as a codiscoverer of dendritic cells (DCs) and as a founding father of the research area that these cells have spawned. For his discovery, Steinman was recently awarded the 2007 Albert Lasker Award for Basic Medical Research. Yet the man behind the research holds his praise for the many other scientists-in the U.S. and abroad-who have further advanced the therapeutic promise of DCs.

Receptor editing: how B cells stay tolerant.

In 1993, David Nemazee and Martin Weigert independently showed that autoreactive B cells could proofread, alter, and reexpress modified receptors to become nonautoreactive. This process, called "receptor editing," has since gained prominence as the main mechanism of B cell tolerance.

CTLA-4: From conflict to clinic.

CTLA-4 was first identified in 1991 as a second receptor for the T cell costimulation ligand B7. Uncertainties about its biological function plagued the early years after its discovery until 1995, when it was confirmed to be an inhibitor of T cell responses. CTLA-4 has since scored in the clinic as a target for antitumor therapy and as a soluble inhibitor of autoimmunity.

Interleukin-12: a master regulator.

Early resistance to pathogens requires a swift response from NK cells. In 1989, Giorgio Trinchieri identified an NK growth factor and activator, later called interleukin-12 (IL-12). This discovery helped reveal the regulatory link between innate and adaptive immunity.

Crossing barriers in transplantation.

In 1978, Jonathan Sprent and Robert Korngold proved that graft-versus-host disease (GVHD) is caused by donor T cells that attack the host's non-MHC antigens. T cell depletion of donor grafts has since become a staple of transplantation strategies to combat leukemia and other inherited blood disorders.

Th1/Th2 cross-regulation and the discovery of IL-10.

In the late 1980s, Tim Mosmann and colleagues isolated functionally distinct T helper (Th)-1 and Th2 clones, and provided evidence that these two subsets were mutually inhibitory. Knowledge of the inhibition led to the discovery that Th2 cells make IL-10 to suppress Th1 cells.

IFNgamma: issuing macrophages a license to kill.

T cells tell macrophages when to start making the toxic soup of lysosomal enzymes, reactive oxygen species, and nitric oxide that destroys intracellular pathogens. In 1983, Carl Nathan proved that this start signal comes in the form of the secreted cytokine IFNgamma.

Dengue virus-reactive CD8+ T cells display quantitative and qualitative differences in their response to variant epitopes of heterologous viral serotypes.

Reactivation of serotype cross-reactive CD8+ memory T lymphocytes is thought to contribute to the immunopathogenesis of dengue disease during secondary infection by a heterologous serotype. Using cytokine flow cytometry, we have defined four novel HLA-A*02-restricted dengue viral epitopes recognized by up to 1.5% of circulating CD8+ T cells in four donors after primary vaccination. All four donors had the highest cytokine response to the epitope NS4b 2353. We also studied the effect of sequence differences in heterologous dengue serotypes on dengue-reactive CD8+ memory T cell cytokine and proliferative responses. The D3 variant of a different NS4b epitope 2423 and the D2 variant of the NS4a epitope 2148 induced the largest cytokine response, compared with their respective heterologous sequences in all donors regardless of the primary vaccination serotype. Stimulation with variant peptides also altered the relative frequencies of the various subsets of cells that expressed IFN-gamma, TNF-alpha, MIP-1beta, and combinations of these cytokines. These results indicate that the prior infection history of the individual as well as the serotypes of the primary and heterologous secondary viruses influence the nature of the secondary response. These differences in the effector functions of serotype cross-reactive memory T cells induced by heterologous variant epitopes, which are both quantitative and qualitative, may contribute to the clinical outcome of secondary dengue infection.