No abstract

HSV-specific CD8+ T cells provide constant immunosurveillance of HSV-1 latently infected neurons in sensory ganglia, and their functional properties are influenced by the presence of latent virus. In this study, we show that ganglionic HSV-specific CD8+ T cells exhibit a higher functional avidity (ability to respond to low epitope density) than their counterparts in noninfected lungs, satisfying a need for memory effector cells that can respond to low densities of viral epitopes on latently infected neurons. We further show that lack of CD4+ T cell help during priming leads to a transient inability to control latent virus, which was associated with a PD-1/PD-L1 mediated reduced functional avidity of ganglionic HSV-specific CD8+ T cells. CD4+ T cells are not needed to maintain CD8+ T cell memory through 34 d after infection, nor do they have a direct involvement in the maintenance of HSV-1 latency.

CD4(+) T cells preferentially mediate HSK, but, in their absence, a high infectious dose of HSV-1 can induce histologically similar but transient HSK that is mediated by CD8(+) T cells.

No abstract

Many important aspects of cancer biology, such as cancer initiation, progression, and metastasis, have been studied in animal models, mostly mice. As long as cancer was considered primarily a genetic disease, the study of transplantable mouse tumors, or even human tumor xenografts in immunocompromised mice, appeared to suffice. Many important genetic events that lead to transformation and in vivo tumor growth were elucidated. However, many even more important factors that determine whether or not the genetic potential of a tumor cell will be realized, such as the host response to the tumor and the tumor microenvironment that influences this response over a long period of time of tumor development, remained untested and unappreciated. This is slowly changing with the advent of molecular techniques that have spurred efforts to engineer better mouse models of human tumors. In this review, we show results of our efforts to combine a genetic mouse model of spontaneous human adenocarcinomas based on a Kras mutation, with an important human molecule MUC1 that is abnormally expressed on human adenocarcinomas, promoting oncogenesis, proinflammatory tumor microenvironment, and immunosurveillance.

Properties of the cornea such as a lack of blood and lymphatic vessels, a lack of professional antigen-presenting cells, and exposure to immunosuppressive factors in the aqueous humor contribute to a relative state of immune privilege. Ironically, corneal damage and the accompanying visual morbidity following herpes simplex virus type 1 (HSV-1) infection does not results from uncontrolled viral replication, but from an immunoinflammatory process referred to as herpes stromal keratitis (HSK). This review highlights changes in the immune-privileged status of the cornea following HSV-1 infection that contribute to HSK.

Approximately 7 days after HSV-1 corneal infection, BALB/c mice develop tissue-destructive inflammation in the cornea termed herpes stromal keratitis (HSK), as well as periocular skin lesions that are characterized by vesicles, edema, and fur loss. CD4+ T cells and Th1 cytokines contribute to both the immunopathology in the cornea and the eradication of viral replication in the skin. We demonstrate that disruption of CD40/CD154 signaling does not impact the initial expansion of CD4+ T cells in the draining lymph nodes, but dramatically reduces the persistence and Th1 polarization of these cells. Despite the reduced Th1 response, CD154−/− mice developed HSK and periocular skin disease with similar kinetics and severity (as assessed by clinical examination) as wild-type (WT) mice. However, when the composition of the inflammatory infiltrate was examined by flow cytometric analysis, CD154−/− mice exhibited significantly fewer CD4+ and CD8+ T cells and neutrophils than WT mice at the peak of HSK. Moreover, CD4+ T cells from infected corneas of CD154−/− mice produced significantly less IFN-γ than those of WT mice when stimulated with viral Ags in vitro. The IFN-γ production of cells from infected corneas of WT mice was not affected by addition of anti-CD154 mAb to the stimulation cultures. This suggests that CD154 signaling is required at the inductive phase, but not at the effector phase, of the Th1 response within the infected cornea. We conclude that local disruption of CD40/CD154 signaling is not likely to be a useful therapy for HSK.

Herpes stromal keratitis (HSK) is an immunopathological disease regulated by Th1 CD4 T cells, which require APC and costimulation within the infected cornea to mediate disease. Recent studies suggest the OX40:OX40 ligand (OX40L) interaction enhances effector cell cytokine secretion at inflammatory sites. OX40(+) cells were detected in HSV-1-infected mouse corneas as early as 3 days postinfection (dpi), prior to the onset of HSK, and their frequency increased through 15 dpi, when all mice exhibited severe HSK. OX40L(+) cells were first detected at 7 dpi, coincident with the initiation of HSK. It is interesting that the OX40L(+) cells did not coexpress MHC Class II or the dendritic cell (DC) marker CD11c. Our findings demonstrate rapid infiltration of activated (OX40(+)) CD4(+) T cells into HSV-1-infected corneas and expression of OX40L on MHC Class II-negative cells but surprisingly, not on MHC Class II(+) CD11c(+) DC, which are present in the infected corneas and required for HSK. Moreover, neither local nor systemic treatment of mice with a blocking antibody to OX40L or with a blocking fusion protein altered the course of HSK significantly, possibly as a result of a lack of OX40L expression on functional APC.