Reactive oxygen species (ROS) are thought to have effects on T-cell function and proliferation. Low concentrations of ROS in T cells are a prerequisite for cell survival, and increased ROS accumulation can lead to apoptosis/ necrosis. The cellular redox state of a T cell can also affect T-cell receptor signaling, skewing the immune response.

T cell cytolytic activity targeting epidermal melanocyte is shown to cause progressive depigmentation and autoimmune vitiligo. Using the recently developed transgenic mice h3TA2 that carry T cell with a HLA-A2 restricted human tyrosinase reactive TCR and develop spontaneous vitiligo from an early age, we addressed the mechanism regulating autoimmune vitiligo. Depigmentation was significantly impaired only in IFN-γ knockout h3TA2 mice but not in TNF-α or perforin knockout h3TA2 mouse strains, confirming a central role for IFN-γ in vitiligo development. Additionally, the regulatory T cells (Treg) were relatively abundant in h3TA2-IFN-γ−/− mice, and depletion of Treg employing anti-CD25 antibody fully restored the depigmentation phenotype in h3TA2-IFN-γ−/− mice mediated in part through upregulation of pro-inflammatory cytokines as IL-17and IL-22. Further therapeutic potential of Treg abundance in preventing progressive depigmentation was evaluated by adoptively transferring purified Treg or using rapamycin. Both adoptive transfer of Treg and rapamycin induced lasting remission of vitiligo in mice treated at the onset of disease, or in mice with established disease. This leads us to conclude that reduced regulatory responses are pivotal to the development of vitiligo in disease-prone mice, and that a quantitative increase in the Treg population may be therapeutic for vitiligo patients with active disease.

Recent advancements in T cell immunotherapy suggest that T cells engineered with high affinity T cell receptors (TCR) can offer better tumor regression. However, whether a high affinity TCR alone is sufficient to control tumor growth, or the T cell subset bearing the TCR is also important remains unclear. Using the human tyrosinase epitope reactive, CD8 independent, high affinity TCR isolated from MHC class-I restricted CD4+ T cells obtained from tumor infiltrating lymphocytes of a metastatic melanoma patient, we developed a novel TCR transgenic mouse with a C57BL/6 background. This HLA-A2 restricted TCR was positively selected on both CD4+ and CD8+ single-positive (SP) cells. However, when the TCR transgenic mouse was developed with an HLA-A2 background, the transgenic TCR was primarily expressed by CD3+CD4-CD8- double-negative (DN) T cells. TIL 1383I TCR transgenic CD4+, CD8+ and CD4-CD8- T cells were functional and retained the ability to control tumor growth without the need for vaccination or cytokine support in vivo. Furthermore, the HLA-A2+/human tyrosinase TCR double transgenic mice developed spontaneous hair depigmentation and had visual defects that progressed with age. Our data show that the expression of the high affinity TIL 1383I TCR alone in CD3+ T cells is sufficient to control the growth of murine and human melanoma and the presence or absence of CD4 and CD8 co-receptors had little effect on its functional capacity.

Apoptosis is a natural process where cells that are no longer required can be eliminated in a highly regulated, controlled manner. Apoptosis is important in maintaining the mammalian immune system and plays a significant role in immune response, positive and negative T cell selection, and cytotoxic death of target cells. When the apoptotic pathways are impaired or are not tightly regulated, autoimmune diseases, inflammatory diseases, viral and bacterial infections and cancers ensue. An imbalance in the anti-apoptotic and pro-apoptotic factors has been implicated in these diseases. Moreover, current therapies directed towards these diseases focus on the modulation of the apoptotic death pathways to regulate the immune response. In this review, we will focus on the process of T cell activation and apoptosis in autoimmune reactions, in response to tumor progression as well as in response to bacterial and viral infections.

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Restoration of epithelial specific proteins, such as E-cadherin, in tumor cells can inhibit invasion. However, invasion is a complex process regulated not only by E and N-cadherin but also by catenin-complex proteins. The complex signaling process associated with tumor invasion warrants further investigation since crosstalk between overlapping signaling pathways is involved in regulating prostate cancer invasion, metastasis and progression.

BackgroundBladder cancer, the 5th most common malignancy in the USA, is often detected as a result of incidental findings or by presenting hematuria. Once diagnosed the disease is one of the costliest cancers to treat due to frequent, invasive and often lifelong follow-up procedures. Because cells are shed into urine, there has been an emerging effort to develop non-invasive tests for the detection of bladder cancer. Expression of survivin, a member of the inhibitor of apoptosis protein family, has been associated with bladder cancer. Therefore, the goal of this study was to determine the feasibility of transducing viable exfoliated cells obtained from urine with an adenoviral vector in which a reporter gene is under the control of the survivin promoter.MethodsExfoliated cells from urine were obtained from 36 human subjects (> 40 years old). An adenovirus in which GFP expression is under control of the survivin promoter (Ad.Surv.GFP) was generated. An adenovirus in which GFP is expressed from the CMV promoter served as a control. GFP expression was analyzed by fluorescent microscopy and quantified by flow cytometry.ResultsShort-term cultures from exfoliated cells in urine could be established in 16 of 31 samples. These cultures were successfully transduced with Ad.CMV.GFP. Analysis of GFP expression following transduction with Ad.Surv.GFP, indicated that the survivin promoter was preferentially active in UM-UC-3 bladder cancer cells compared to non-malignant UROtsa cells. Interestingly, baseline levels of GFP expression in cultures from exfoliated cells in urine exhibited higher baseline levels than UROtsa following transduction with Ad.Surv.GFP.ConclusionsWe demonstrated the feasibility of establishing and analysing short-term cultures isolated from exfoliated cells in voided urine by means of adenoviral transduction, thereby forming the foundation for future studies to determine the specificity and sensitivity of a non-invasive test based on survivin promoter activity.

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