Cadherins play an important role in tissue homeostasis, as they are responsible for cell-cell adhesion during embryogenesis, tissue morphogenesis, differentiation and carcinogenesis. Cadherins are inseparably connected with catenins, forming cadherin-catenin complexes, which are crucial for cell-to-cell adherence. Any dysfunction or destabilization of cadherin-catenin complex may result in tumor progression. Epithelial mesenchymal transition (EMT) is a mechanism in which epithelial cadherin (E-cadherin) expression is lost during tumor progression. However, during tumorigenesis, many processes take place, and downregulation of E-cadherin, nuclear β-catenin and p120 catenin (p120) signaling are among the most critical. Additional signaling pathways, such as Receptor tyrosine kinase (RTK), Rho GTPases, phosphoinositide 3-kinase (PI3K) and Hippo affect cadherin cell-cell adhesion and also contribute to tumor progression and metastasis. Many signaling pathways may be activated during tumorigenesis; thus, cadherin-targeting drugs seem to limit the progression of malignant tumor. This review discusses the role of cadherins in selected signaling mechanisms involved in tumor growth. The clinical importance of cadherin will be discussed in cases of human and animal cancers.

It has become evident that naturally occurring CD25⁺regulatory T cells (T_regcells) 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_regcell response is curtailed during either primary or recall immunization. The data presented here show that removal of CD25⁺T_regcells 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_regcell-depleted animals was between two- and threefold and evident in both acute and memory stages. Interestingly, removal of CD25⁺T_regcells 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_regcells cleared the virus more effectively compared with control groups. We conclude that CD25⁺T_regcells 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_regcells and if it is possible to devise means of limiting T_regcell activity to enhance vaccine efficacy.

γδ T cells are the majority peripheral blood T cells in young cattle. The role of γδ T cells in innate responses against infection with foot-and-mouth disease virus was analyzed on consecutive 5 d following infection. Before infection, bovine WC1⁺ γδ T cells expressed a nonactivated phenotype relative to CD62L, CD45RO, and CD25 expression and did not produce IFN-γ ex vivo. Additionally, CD335 expression was lacking and no spontaneous target cell lysis could be detected in vitro, although perforin was detectable at a very low level. MHC class II and CD13 expression were also lacking. Following infection with foot-and-mouth disease virus, expression of CD62L and CD45RO was greatly reduced on WC1⁺ γδ T cells, and unexpectedly, CD45RO expression did not recover. A transient increase in expression of CD25 correlated with production of IFN-γ. Expression of CD335 and production of perforin were detected on a subset of γδ T cells, and this correlated with an increased spontaneous killing of xenogeneic target cells. Furthermore, increased MHC class II expression was detected on WC1⁺ γδ T cells, and these cells processed protein Ags. These activities are rapidly induced, within 3 d, and wane by 5 d following infection. All of these functions, NK-like killing, Ag processing, and IFN-γ production, have been demonstrated for these cells in various species. However, these results are unique in that all these functions are detected in the same samples of WC1⁺ γδ T cells, suggesting a pivotal role of these cells in controlling virus infection.

Foot-and-mouth disease (FMD) continues to be a significant threat to the health and economic value of livestock species. This acute infection is caused by the highly contagious FMD virus (FMDV), which infects cloven-hoofed animals, including large and small ruminants and swine. Current vaccine strategies are all directed toward the induction of neutralizing antibody responses. However, the role of cytotoxic T lymphocytes (CTLs) has not received a great deal of attention, in part because of the technical difficulties associated with establishing a reliable assay of cell killing for this highly cytopathic virus. Here, we have used recombinant human adenovirus vectors as a means of delivering FMDV antigens in a T cell-directed vaccine in pigs. We tested the hypothesis that impaired processing of the FMDV capsid would enhance cytolytic activity, presumably by targeting all proteins for degradation and effectively increasing the class I major histocompatibility complex (MHC)/FMDV peptide concentration for stimulation of a CTL response. We compared such a T cell-targeting vaccine with the parental vaccine, previously shown to effectively induce a neutralizing antibody response. Our results show induction of FMDV-specific CD8 ⁺ CTL killing of MHC-matched target cells in an antigen-specific manner. Further, we confirm these results by MHC tetramer staining. This work presents the first demonstration of FMDV-specific CTL killing and confirmation by MHC tetramer staining in response to vaccination against FMDV.

Foot-and-mouth disease virus (FMDV) causes an acute, highly contagious disease of livestock. Though FMDV is very sensitive to interferon-alpha (IFN-alpha), IFN-beta, and IFN-gamma, the virus has evolved mechanisms to evade such innate responses. For instance, during acute infection, FMDV suppresses IFN-alpha production by skin and myeloid dendritic cells (DCs). We have previously reported that FMDV infection induces a transient lymphopenia and interruption of T-lymphocyte responses to mitogenic stimuli. To further understand the immunopathogenesis of FMD, we have now analyzed the serum IFN-alpha response in relation to lymphopenia, and the number and function of plasmacytoid DCs (pDCs) following infection of pigs with multiple serotypes of FMDV. Serum IFN-alpha peaked 2-3 d post-infection (PI), regardless of FMDV serotype. Lymphopenia coincided with peak viremia and the serum IFN-alpha response. Circulating pDC numbers and in-vitro pDC IFN-alpha secretion transiently declined by 48 h following infection. Infection of lymphocytes or pDCs was never detected regardless of the FMDV serotype inoculated or the age of the animal infected. These data indicate that, like other DC subsets, there is suppression of interferon production by pDCs, which abrogates this important innate response. Rapid induction of serum IFN-alpha, albeit short-lived, may contribute to the rapid resolution of FMDV viremia prior to induction of specific immunity.

Viruses have evolved multiple mechanisms to evade the innate immune response, particularly the actions of interferons (IFNs). We have previously reported that exposure of dendritic cells (DCs) to foot-and-mouth disease virus (FMDV) in vitro yields no infection and induces a strong type I IFN (IFN-alpha and IFN-beta) response, indicating that DCs may play a critical role in the innate response to the virus. In vivo, FMDV induces lymphopenia and reduced T-cell proliferative responses to mitogen, viral effects that may contribute to evasion of early immune responses. In this study we analyzed the in vivo effects of FMDV infection on the IFN-alpha response of two populations of dendritic cells. During the acute phase of infection of swine, production of IFN-alpha from monocyte-derived DCs (MoDCs) and skin-derived DCs (skin DCs) is inhibited. This effect occurs concurrently with rising viral titers in the blood; however, these cells are not productively infected. Interestingly, there are no changes in the capability of these DCs to take up particles and process antigens, indicating that antigen-presenting cell function is normal. These data indicate that inhibition of the IFN-alpha response of dendritic cell populations from blood and skin by FMDV enhances viral pathogenesis in infected animals.