Homeostatic expansion of CD4(+) T cells upregulates VLA-4 and exacerbates HSV-induced corneal immunopathology

Using a viral-induced immunopathology model, we showed that when CD4(+) T cells were allowed to undergo homeostatic expansion prior to ocular herpes simplex virus infection, mice developed more severe inflammatory lesions with the increased severity associated with enhanced effector function of ocular CD4(+) T cells, and blocking their functional activity reduced the lesion severity. Additionally, homeostatically expanded CD4(+) T cells upregulated VLA-4, and in vivo administration of anti-VLA-4 mAb significantly decreased the homeostatic proliferation. Furthermore, blocking of VLA-4 interaction also diminished the infiltration of CD4(+) T cells into the cornea and decreased lesion severity. Our results imply that homeostatic expansion of T cells, as could occur in a virus-induced lymphopenia, may generate cells with enhanced effector function that can contribute to tissue damage.     

Application of plasmid DNA encoding IL-18 diminishes development of herpetic stromal keratitis by antiangiogenic effects

HSV-1 infection of the eye can cause a blinding immunoinflammatory stromal keratitis (SK) lesion. Using the mouse model, we have demonstrated that angiogenesis is an essential step in lesion pathogenesis because its inhibition results in diminished severity. The molecules involved in causing corneal angiogenesis are multiple and include the vascular endothelial growth factor (VEGF) family of proteins. In this report we show that application of plasmid DNA encoding IL-18 to the cornea of mice before HSV-1 ocular infection resulted in reduced angiogenesis and diminished SK immunoinflammatory lesions. The antiangiogenic effects of IL-18 treatment appeared to be mediated by inhibition of VEGF production in the cornea. We also showed that IL-18 controlled VEGF expression in vitro and also decreased CpG oligodeoxynucleotide induced VEGF-dependent neovascularization. In addition the administration of IL-18-binding protein, an IL-18 antagonist, into the inflammatory eye resulted in elevated angiogenesis and increased VEGF expression. Our results indicate that IL-18 is an important endogenous negative regulator of HSV-induced angiogenesis resulting in reduced SK lesion severity. Our results could mean that IL-18 administration may represent a useful approach to manage unwanted angiogenesis.     

Parameter estimation from experimental laboratory data of HSV-1 by using alternative regression method

In this paper, an estimation of model parameters is performed by using the Alternative Regression (AR) approach on an experimental data set of Herpes Simplex Virus type-1 (HSV-1) infection with innate immune response. Throughout the specified course of time, the measurements of monocytes, neutrophils, and viral load were obtained from the corneas of infected mice. C57BL/6 (B6) mice were used at Oakland University, Department of Biological Sciences, and the outcome measurements were divided into training and testing data sets. The HSV-1 nonlinear dynamic model is proposed based on the observed data patterns and biological system information. The simulation results of the proposed model showed that they consistently fit the experimental data set. In addition, the sensitivity test and model validation diagnostics are considered to determine the most significant key parameters that affect the dynamics of the HSV-1 system.     

IL-10 and natural regulatory T cells: two independent anti-inflammatory mechanisms in herpes simplex virus-induced ocular immunopathology

Two prominent anti-inflammatory mechanisms involved in controlling HSV-1-induced corneal immunopathology (stromal keratitis or SK) are the production of the cytokine IL-10 and the activity of natural regulatory T cells (nTregs). It is not known whether, under in vivo conditions, IL-10 and nTregs influence the corneal pathology independently or in concert. In the current study using wild-type and IL-10(-/-) animals, we have assessed the activity of nTregs in the absence of IL-10 both under in vitro and in vivo conditions. The IL-10(-/-) animals depleted of nTregs before ocular infection showed more severe SK lesions as compared with the undepleted IL-10(-/-) animals. In addition, nTregs purified from naive WT and IL-10(-/-) animals were equally able to suppress the proliferation and the cytokine production from anti-CD3-stimulated CD4(+)CD25(-) T cells in vitro. Furthermore, intracellular cytokine staining results indicated that nonregulatory cells expressing B220 and CD25 markers were the major IL-10-producing cell types in the lymphoid tissues of HSV-infected mice. In contrast, in the infected corneas, cells with the CD11b(+)Gr1(+) phenotype along with a minor population of Foxp3(-)CD4(+) and a few F4/80(+) cells produced IL-10. Our current investigations indicate that at least two independent anti-inflammatory mechanisms are involved in limiting the corneal lesions in SK, both of which may need to be modulated to control SK therapeutically.     

CD4+ CD25+ T cells regulate vaccine-generated primary and memory CD8+ T-cell responses against herpes simplex virus type 1

It has become evident that naturally occurring CD25(+) regulatory T cells (T(reg) cells) not only influence self-antigen specific immune response but also dampen foreign antigen specific immunity. This report extends our previous findings by demonstrating that immunity to certain herpes simplex virus (HSV) vaccines is significantly elevated and more effective if T(reg) cell response is curtailed during either primary or recall immunization. The data presented here show that removal of CD25(+) T(reg) cells prior to SSIEFARL-CpG or gB-DNA immunization significantly enhanced the resultant CD8(+) T-cell response to the immunodominant SSIEFARL peptide. The enhanced CD8(+) T-cell reactivity in T(reg) cell-depleted animals was between two- and threefold and evident in both acute and memory stages. Interestingly, removal of CD25(+) T(reg) cells during the memory recall response to plasmid immunization resulted in a twofold increase in CD8(+) T-cell memory pool. Moreover, in the challenge experiments, memory CD8(+) T cells generated with plasmid DNA in the absence of T(reg) cells cleared the virus more effectively compared with control groups. We conclude that CD25(+) T(reg) cells quantitatively as well as qualitatively affect the memory CD8(+) T-cell response generated by gB-DNA vaccination against HSV. However, it remains to be seen if all types of vaccines against HSV are similarly affected by CD25(+) T(reg) cells and if it is possible to devise means of limiting T(reg) cell activity to enhance vaccine efficacy.     

Regulatory cells and infectious agents: detentes cordiale and contraire

This brief review describes the types of interactions that occur between CD4(+)CD25(+) regulatory T cells (Treg) and microbial pathogens. These interactions range from one of mutual benefit (détente cordiale) such as occurs in Leishmania major infection of resistant mouse strains, to instances where the Treg response appears to mainly favor the pathogen and be detrimental to the host (détente contraire). Examples of the latter include chronic persistent infections with retroviruses, perhaps including HIV, and hepatitis C virus. The Treg response also hampers the effectiveness of immunity against some acute virus infections such as HSV. Evidence is also discussed showing that Treg can play a benevolent role to limit the severity of bystander tissue damage in circumstances where the immune response to pathogens is immunopathological. Finally, emerging approaches are discussed that either blunt or activate Treg and that could be used practically to manage host-pathogen interaction.