Reactivation of latent herpes simplex virus 2 (HSV-2) infections can be characterized by episodic recurrent genital lesions and/or viral shedding. We hypothesize that infected (HSV-2(pos)) asymptomatic individuals have acquired T cell responses to specific HSV-2 antigen(s) that may be an important factor in controlling their recurrent disease symptoms. Our proteomic screening technology, ATLAS, was used to characterize the antigenic repertoire of T cell responses in infected (HSV-2(pos)) and virus-exposed seronegative (HSV-2(neg)) subjects. T cell responses, determined by IFN-γ secretion, were generated to gL, UL2, UL11, UL21, ICP4, ICP0, ICP47 and UL40 with greater magnitude and/or frequency among cohorts of exposed HSV-2(neg) or asymptomatic HSV-2(pos) individuals, compared to symptomatic recurrent HSV-2(pos) subjects. T cell antigens recognized preferentially among individuals who are resistant to infection or who are infected and have mild or no clinical disease may provide new targets for the design of vaccines aimed at treating and/or preventing HSV-2 infection.
Exogenously delivered antigenic peptides complexed to heat shock proteins (HSPs) are able to enter the endogenous Ag-processing pathway and prime CD8+ CTL. It was determined previously that a hybrid peptide containing a MHC class I-binding epitope and HSP70-binding sequence Javelin (J0) in complex with HSP70 could induce cytotoxic T cell responses in vivo that were more robust than those induced by the minimal epitope complexed with HSP70. The present study introduces a novel, higher-affinity HSP70-binding sequence (J1) that significantly enhances binding of various antigenic peptides to HSP70. A competition binding assay revealed a dissociation constant that was 15-fold lower for the H2-Kb OVA epitope SIINFEKL-J1 compared with SIINFEKL-J0, indicating a substantially higher affinity for HSP70. Further, modifying the orientation of the hybrid epitope and introducing a cleavable linker sequence between the Javelin and the epitope results in even greater immunogenicity, presumably by greater efficiency of epitope processing. The enhanced immunogenicity associated with Javelin J1 and the cleavable linker is consistently observed with multiple mouse and human epitopes. Thus, by creating a series of epitopes with uniform, high-affinity binding to HSP70, successful multiple epitope immunizations are possible, with equal delivery of each antigenic epitope to the immune system via HSP70. These modified epitopes have the potential for creating successful multivalent vaccines for immunotherapy of both infectious disease and cancer.
dChlamydia trachomatis is the causative agent of the most frequently reported bacterial sexually transmitted infection, the total burden of which is underestimated due to the asymptomatic nature of the infection. Untreated C. trachomatis infections can cause significant morbidities, including pelvic inflammatory disease and tubal factor infertility (TFI). The human immune response against C. trachomatis, an obligate intracellular bacterium, is poorly characterized but is thought to rely on cell-mediated immunity, with CD4؉ and CD8 ؉ T cells implicated in protection. In this report, we present immune profiling data of subjects enrolled in a multicenter study of C. trachomatis genital infection. CD4؉ and CD8 ؉ T cells from subjects grouped into diseasespecific cohorts were screened using a C. trachomatis proteomic library to identify the antigen specificities of recall T cell responses after natural exposure by measuring interferon gamma (IFN-␥) levels. We identified specific T cell responses associated with the resolution of infection, including unique antigens identified in subjects who spontaneously cleared infection and different antigens associated with C. trachomatis-related sequelae, such as TFI. These data suggest that novel and unique C. trachomatis T cell antigens identified in individuals with effective immune responses can be considered as targets for vaccine development, and by excluding antigens associated with deleterious sequelae, immune-mediated pathologies may be circumvented.
Immune responses are mediated by innate immune cells (e.g., macrophages) and subsequently, adaptive immune cells (e.g., B cells). Macrophages secrete an array of cytokines to effect their functions in host defense, tissue repair and immunoregulation. Pro-inflammatory macrophages (M1) produce cytokines, such as IL-12p70, TNF-α, IL-6, IL-1β, IL-12p40, IL-23, IFN-γ, and IP-10, while anti-inflammatory and tissue repairing macrophages (M2) release a different set of factors, such as IL-4, IL-10, IL-6, Arginase, TARC and IL-1RA. B cells, in addition to antibody production, also secrete an array of cytokines that mediate Th1- and Th2-like immune responses. These cytokines are produced by regulatory B cells (e.g., IL-10, TGF-β1) and B effector cells, namely Be1 (e.g., TNF-α, TNF-β, IFN-γ, and IL-12p70) and Be2 cells (e.g., IL-2, IL-4, IL-6, TNF-α, and IL-13). Other cytokines associated with activation and survival of B cells such as APRIL, BAFF, and CD40L are also important targets in B cell related processes. We have developed new assay panels targeting macrophage/microglia and B cells, using fluorescence–encoded beads that are suitable for use on general lab flow cytometers. Each panel allows simultaneous quantification of 13 related analytes as shown below. PanelTargetMacrophage/MicrogliaIL-1β, 1RA, 4, 6, 10, 12p40, 12p70, 23, IFN-γ, TARC, TNF-α, Arginase, IP-10B cellIL-2, 4, 6, 10, 12p70, 13, 17A, IFN-γ, TNF-α, TNF-β, BAFF, APRIL, CD40L These panels have been validated by detecting expected changes in biological samples. These high quality, low cost and ease of use panels provide an alternative multiplex solution to the biomedical research community.
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