No abstract

Significantly higher levels of plasma CXCL13 [chemokine (C-X-C motif) ligand 13] were associated with the generation of broadly neutralizing antibodies (bnAbs) against HIV in a large longitudinal cohort of HIV-infected individuals. Germinal centers (GCs) perform the remarkable task of optimizing B-cell Ab responses. GCs are required for almost all B-cell receptor affinity maturation and will be a critical parameter to monitor if HIV bnAbs are to be induced by vaccination. However, lymphoid tissue is rarely available from immunized humans, making the monitoring of GC activity by direct assessment of GC B cells and germinal center CD4 + T follicular helper (GC Tfh) cells problematic. The CXCL13-CXCR5 [chemokine (C-X-C motif) receptor 5] chemokine axis plays a central role in organizing both B-cell follicles and GCs. Because GC Tfh cells can produce CXCL13, we explored the potential use of CXCL13 as a blood biomarker to indicate GC activity. In a series of studies, we found that plasma CXCL13 levels correlated with GC activity in draining lymph nodes of immunized mice, immunized macaques, and HIV-infected humans. Furthermore, plasma CXCL13 levels in immunized humans correlated with the magnitude of Ab responses and the frequency of ICOS + (inducible T-cell costimulator) Tfh-like cells in blood. Together, these findings support the potential use of CXCL13 as a plasma biomarker of GC activity in human vaccine trials and other clinical settings.T he germinal center (GC) reaction is a critical immunological process that occurs in draining lymph nodes after immunization (1). The GC response consists of antigen-specific B cells undergoing affinity maturation through a process of somatic hypermutation (SHM) of the B-cell receptor. SHM is necessary for producing high-affinity Ab responses after immunizations and infections. Influenza neutralizing Abs have substantial SHM. Particularly high levels of SHM, 15-30% amino acid mutation (2, 3), are present and necessary for broad Ab neutralization of diverse HIV strains (4, 5). Therefore, as candidate influenza and HIV vaccines are evaluated for the ability to induce broadly neutralizing antibodies (bnAbs), the quantitation and functional characterization of GC responses will be a key parameter for study. Serological analysis of vaccine-specific Ab titers provides important information, but those data are limited. Serological outcomes are measured at time points long after initial immunizations. Neutralizing Ab responses are commonly only measurable after multiple boosts. Those outcomes likely depend on GC activity and affinity maturation at much earlier time points. Several state of the art HIV vaccine strategies rely on long, multistage immunization protocols (6, 7). With bnAb responses as the goal, means of early analysis of the immune response will be essential to understand and improve on vaccination schemes that may end in failure or only partial success. One critical parameter to assess will be the ability of each immunization to generate GC responses.Central to the GC re...

Interferon (IFN)-γ is necessary for tumor immunity, however, its initial cellular source is unknown. Because γδ T cells primarily produce this cytokine upon activation, we hypothesized that they would provide an important early source of IFN-γ in tumor immunosurveillance. To address this hypothesis, we first demonstrated that γδ T cell–deficient mice had a significantly higher incidence of tumor development after challenge with a chemical carcinogen methylcholanthrene (MCA) or inoculation with the melanoma cell line B16. In wild-type mice, γδ T cells were recruited to the site of tumor as early as day 3 after inoculation, followed by αβ T cells at day 5. We then used bone marrow chimeras and fetal liver reconstitutions to create mice with an intact γδ T cell repertoire but one that was specifically deficient in the capacity to produce IFN-γ. Such mice had a higher incidence of tumor development, induced either with MCA or by inoculation of B16 melanoma cells, compared with mice with IFN-γ–competent γδ T cells. Moreover, genetic deficiency of γδ T cells resulted in impaired IFN-γ production by tumor antigen-triggered αβ T cell upon immunization with tumor lysate. These results demonstrate that γδ T cells can play a necessary role in tumor immunity through provision of an early source of IFN-γ that in turn may regulate the function of tumor-triggered αβ T cells.

West Nile (WN) virus causes fatal meningoencephalitis in laboratory mice, thereby partially mimicking human disease. Using this model, we have demonstrated that mice deficient in γδ T cells are more susceptible to WN virus infection. TCRδ−/− mice have elevated viral loads and greater dissemination of the pathogen to the CNS. In wild-type mice, γδ T cells expanded significantly during WN virus infection, produced IFN-γ in ex vivo assays, and enhanced perforin expression by splenic T cells. Adoptive transfer of γδ T cells to TCRδ−/− mice reduced the susceptibility of these mice to WN virus, and this effect was primarily due to IFN-γ-producing γδ T cells. These data demonstrate a distinct role for γδ T cells in the control of and prevention of mortality from murine WN virus infection.