The role of autoimmune regulator (Aire) in the development of the immune system

AIRE is the gene responsible for a rather rare hereditary type of autoimmune disease. The mechanism underlying the autoimmune pathogenesis caused by AIRE deficiency is a focus of intense research because it could provide clues to the fundamental question of how the immune system discriminates between self and non-self within the thymic microenvironment.     

The My(c)stery of iNKT cell ontogeny

Invariant Vα14 bearing natural killer T cells (iNKT) cells constitute a subset of lymphocytes that recognize lipid-based ligands presented by the non-classical MHC class I-like molecule CD1d and responds with rapid cytokine production. Despite their multiple implications in regulating immune responses, pertaining to cancer and auto-immunity, the molecular requirements for their development in the thymus are poorly understood. Here we discuss recent evidence that c-Myc mediates an intrathymic proliferation wave immediately following agonist selection of iNKT cells that is vital for the generation of mature iNKT cells in vivo. We review aspects of early iNKT ontogeny in light of our findings and speculate about possible mechanistic links controlling c-Myc activity in newly selected cells.     

Pbrm1 intrinsically controls the development and effector differentiation of iNKT cells

Under static condition, the pool size of peripheral invariant natural killer T (iNKT) cells is determined by their homeostatic proliferation, survival and thymic input. However, the underlying mechanism is not fully understood. In the present study, we found that the percentage and number of iNKT cells were significantly reduced in the spleen, but not in the thymus of mice with deletion of polybromo‐1 (Pbrm1) compared to wild type (WT) mice. Pbrm1 deletion did not affect iNKT cell proliferation and survival, instead significantly impaired their development from stage 1 to stage 2. Importantly, loss of Pbrm1 led to a dysfunction of RORγt expression and iNKT17 cell differentiation, but not iNKT1 and iNKT2 proportion. Collectively, our study reveals a novel mechanism of Pbrm1 controlling the peripheral size of iNKT cells through regulating their development and differentiation.     

Subcellular location and expression pattern of autoimmune regulator (Aire), the mouse orthologue for human gene defective in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED).

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome Type I (APS1), is an autosomal recessive autoimmune disease caused by mutations in a gene designated as AIRE (autoimmune regulator). Here we have studied the expression of Aire in transfected cell lines and in adult mouse tissues. Our results show that Aire has a dual subcellular location and that it is expressed in multiple immunologically relevant tissues such as the thymus, spleen, lymph nodes, and bone marrow. In addition, Aire expression was detected in various other tissues such as kidney, testis, adrenal glands, liver, and ovary. These findings suggest that APECED protein might also have a function(s) outside the immune system.(J Histochem Cytochem 49:197-208, 2001)     

Stigma/style cell cycle inhibitor 1 (SCI1), a tissue-specific cell cycle regulator that controls upper pistil development

A cDNA encoding a small lysine-rich protein of unknown function was identified in a tobacco (Nicotiana tabacum) stigma/style suppression subtractive hybridization cDNA library. After its characterization, the corresponding gene was designated stigma/style cell cycle inhibitor 1 (SCI1). Fluorescence microscopy with an SCI1-GFP protein fusion demonstrated its nuclear localization, which was confined to the interchromatic region. Real-time RT-PCR and in situ hybridization experiments showed that SCI1 is stigma/style-specific and developmentally regulated. SCI1 RNAi knockdown and overexpression plants had stigmas/styles with remarkably enlarged and reduced areas, respectively, which was attributable to differences in cell numbers. These results indicate that SCI1 is a tissue-specific negative cell cycle regulator. The differences in cell division had an effect on the timing of the differentiation of the stigmatic papillar cells, suggesting that their differentiation is coupled to stigma cell divisions. This is consistent with a role for SCI1 in triggering differentiation through cell proliferation control. Our results revealed that SCI1 is a novel tissue-specific gene that controls cell proliferation/differentiation, probably as a component of a developmental signal transduction pathway.     

Mitochondria-responsive signaling between egg and central cell controls their coordinated maturation

Recent studies suggest a complex regulatory network in female gametophyte of angiosperm. The cell-cell communication between female gametes was confirmed during their maturation and functional specialization. The mitochondria-responsive signaling may play a critical role in this process. Here, we briefly summarized the recent discussion on this topic and proposed a two-pathway’s mechanism for regulating coordinated development of the female gamete cells.     

Janus-like role of regulatory iNKT cells in autoimmune disease and tumour immunity

Invariant CD1D-restricted natural killer T (iNKT) cells function during innate and adaptive immunity and regulate numerous immune responses, such as autoimmune disease, tumour surveillance, infectious disease and abortions. However, the molecular basis of their functions and the nature of disease-associated defects of iNKT cells are unclear and have been the subject of recent controversy. Here, we review recent findings that underscore the potential importance of interactions between iNKT cells and dendritic cells (DCs) that indicate that iNKT cells regulate DC activity to shape both pro-inflammatory and tolerogenic immune responses. The ability to modulate iNKT-cell activity in vivo using the ligand alpha-galactosylceramide and to treat patients with autoimmune disease or cancer is evaluated also.     

Molecular regulation of mast cell development and maturation

Mast cells play a crucial role in the pathogenesis of allergic diseases. In recent years, tremendous progresses have been made in studies of mast cell origination, migration, proliferation, maturation and survival, and the cytokines regulating these activities. These advances have significantly improved our understandings to mast cell biology and to the molecular mechanisms of mast cells in the pathogenesis of allergic diseases.