Enhancing T Cell Immune Responses by B Cell-based Therapeutic Vaccine Against Chronic Virus Infection

Chronic virus infection leads to the functional impairment of dendritic cells (DCs) as well as T cells, limiting the clinical usefulness of DC-based therapeutic vaccine against chronic virus infection. Meanwhile, B cells have been known to maintain the ability to differentiate plasma cells producing antibodies even during chronic virus infection. Previously, alpha-galactosylceramide (alphaGC) and cognate peptide-loaded B cells were comparable to DCs in priming peptide-specific CD8+ T cells as antigen presenting cells (APCs). Here, we investigated whether B cells activated by alphaGC can improve virus-specific T cell immune responses instead of DCs during chronic virus infection. We found that comparable to B cells isolated from naive mice, chronic B cells isolated from chronically infected mice with lymphocytic choriomeningitis virus (LCMV) clone 13 (CL13) after alphaGC-loading could activate CD1d-restricted invariant natural killer T (iNKT) cells to produce effector cytokines and upregulate co-stimulatory molecules in both naive and chronically infected mice. Similar to naive B cells, chronic B cells efficiently primed LCMV glycoprotein (GP) 33-41-specific P14 CD8+ T cells in vivo, thereby allowing the proliferation of functional CD8+ T cells. Importantly, when alphaGC and cognate epitope-loaded chronic B cells were transferred into chronically infected mice, the mice showed a significant increase in the population of epitope-specific CD8+ T cells and the accelerated control of viremia. Therefore, our studies demonstrate that reciprocal activation between alphaGC-loaded chronic B cells and iNKT cells can strengthen virus-specific T cell immune responses, providing an effective regimen of autologous B cell-based therapeutic vaccine to treat chronic virus infection.

Allergen and chow-protein stimulated splenocyte cytokine productions in buckwheat allergic mice / 천식및알레르기

BACKGROUND AND OBJECTIVE: Normal gut immune response to ingestive food proteins is induction of immune tolerance rather than sensitization, even in atopic individuals. Very restricted kinds of food antigens have been known to cause allergic sensitization in humans. To evaluate the differences of systemic T-cell immune responses to sensitized antigen and regular chow-protein, we performed this study. SUBJECTS AND METHODS: Eight naive female, 5-week-old C3H/HeJ mice were grown under the regular mouse chow feeding condition for 4 weeks. During that period, Group I mice were sensitized with buckwheat extract(1mg/dose) mixed with cholera toxin(10 microgram/dose) by intragastric administration at day1, 2, 3, 7, and 21. The sera were obtained at weekly intervals to measure buckwheat-specific and chow-protein-specific IgE, IgG1 and IgG2a antibodies. Splenocyte proliferation assays and cytokine productions were evaluated with buckwheat. chow-protein. and Con A stimulation. Levels of antibodies (IgE, IgG1, IgG2a) and cytokines (IL-4, IL-10, IL-12, INF-gamma were measured by ELISA. RESULTS: The levels of buckwheat specific IgE, IgG1 and IgG2a were markedly increased in Group I mice, but not in Group II mice. Chow-protein specific IgE and IgG1 antibodies were not increased in both groups of mice. The degrees of buckwheat-specific and chow-protein-specific splenocyte proliferations showed low-grade(SI: 6.68 and 4.48. respectively) compared to those by Con A stimulation(SI : 58). Buckwheat stimulated IL-4 productions were markedly increased in Group I mice, which were higher than Con A stimulated production. INF-gamma production was increased in Group I mice by buckwheat stimulation, and in both groups of mice by Con A stimulation. IL-12 production was shown in Con A stimulated culture supernatants in both groups of mice, but in Group I mice with buckwheat stimulation. IL-10 productions were increased in Group I mice with buckwheat, Con A, and chow-protein stimulations, furthermore, markedly increased IL-10 levels were also shown in chow-protein stimulated splenocyte cultures in both groups of mice. CONCLUSION: While Th1 and Th2 immune responses were induced by intragastricly sensitized buckwheat extract, only regulatory immune responses were dominated by regular chow proteins in this system. The minimum ability of chow-protein specific splenocyte proliferation was preserved and IL-10 was the unique cytokine produced by chow-protein simulation.