RESUMO
Mucosal-associated invariant T (MAIT) cells are a subpopulation of innate-like T cells that can be found throughout the body, predominantly in mucosal sites, the lungs and in the peripheral blood. MAIT cells recognize microbial-derived vitamin B (e.g., riboflavin) metabolite antigens that are presented by the major histocompatibility complex class I-like protein, MR1, found on a variety of cell types in the periphery and the CNS. Since their original discovery, MAIT cells have been studied predominantly in their roles in diseases in the periphery; however, it was not until the early 2000s that these cells were first examined for their contributions to disorders of the CNS, with the bulk of the work being done within the past few years. Currently, the MR1/MAIT cell axis has been investigated in only a few neurological diseases including, multiple sclerosis and experimental autoimmune encephalomyelitis, brain cancer/tumors, ischemia, cerebral palsy, general aging and, most recently, Alzheimer's disease. Each of these diseases demonstrates a role for this under-studied innate immune axis in its neuropathology. Together, they highlight the importance of studying the MR1/MAIT cell axis in CNS disorders. Here, we review the contributions of the MR1/MAIT cell axis in the progression or remission of these neurological diseases. This work has shed some light in terms of potentially exploiting the MR1/MAIT cell axis in novel therapeutic applications.
Assuntos
Doenças do Sistema Nervoso Central , Células T Invariantes Associadas à Mucosa , Humanos , Antígenos de Histocompatibilidade Menor/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Riboflavina/metabolismo , Doenças do Sistema Nervoso Central/metabolismoRESUMO
Keratins 5/14 (K5/14) are intermediate filament proteins expressed in the basal layer of stratified epithelial cells and are known targets of p63. Previous research in our laboratory showed that upon K5/14 downregulation in oral squamous cell carcinoma (OSCC)derived cells, there was an increase in intracellular Notch1 levels and differentiation markers such as involucrin, keratin 1 and a decrease in tumorigenic potential in vivo. However, the molecules involved in the K14 regulated cell differentiation and transformation are not known to date. In order to understand the possible role of TAp63, we downregulated TAp63 in a K14knockdown background. We observed that there was a decrease in the expression of Notch1. Expression levels of differentiation markers such as involucrin, K1, loricrin and filaggrin were also decreased. Furthermore, TAp63 downregulation led to an increase in invasion, migration and in vivo tumorigenic potential of these cells. We observed a decrease in ßcatenin signaling in K14downregulated cells. Notably, when TAp63 was downregulated in K14knockdown cells, there was increase in nonphospho ßcatenin levels. Hence, this study indicates that TAp63 plays an important role in K14downregulated cells possibly by regulating the Notch1 expression. K14 regulates the expression of TAp63 which in turn regulates expression of Notch1. The present study is a step forward in our quest to understand the functional significance of molecules that regulate the process of differentiation and tumorigenesis in stratified epithelial cells.