BCL6
B-cell lymphoma 6 protein (BCL-6) (B-cell lymphoma 5 protein) (BCL-5) (Protein LAZ-3) (Zinc finger and BTB domain-containing protein 27) (Zinc finger protein 51) [BCL5] [LAZ3] [ZBTB27] [ZNF51]
Publications[править]
Vaccination is a mainstay in preventive medicine, reducing morbidity and mortality from infection, largely by generating pathogen-specific neutralizing antibodies. However, standard immunization strategies are insufficient with increasing age due to immunological impediments, including defects in T follicular helper (Tfh) cells. Here, we found that Tfh generation is inversely linked to the expression of the ecto-NTPDase CD39 that modifies purinergic signaling. The lineage-determining transcription factor BCL6 inhibited CD39 expression, while increased Tfh frequencies were found in individuals with a germline polymorphism preventing transcription of ENTPD1, encoding CD39. In in vitro human and in vivo mouse studies, Tfh generation and germinal center responses were enhanced by reducing CD39 expression through the inhibition of the cAMP/PKA/p-CREB pathway, or by blocking adenosine signaling downstream of CD39 using the selective adenosine A2a receptor antagonist istradefylline. Thus, purinergic signaling in differentiating T cells can be targeted to improve vaccine responses, in particular in older individuals who have increased CD39 expression.
Keywords
- Adaptive immunity
- Aging
- Cellular senescence
- T cells
- Vaccines
T follicular helper (T ) cells have emerged as a critical limiting factor for controlling the magnitude of neonatal germinal center (GC) reactions and primary vaccine antibody responses. We compared the functional attributes of neonatal and adult T cells at the transcriptomic level and demonstrated that the T cell program is well-initiated in neonates although the T gene-expression pattern (i.e., [i]CXCR5, IL-21, BCL6, TBK1, STAT4, ASCL2[/i], and [i]c-MAF[/i]) is largely underrepresented as compared to adult T cells. Importantly, we identified a TH2-bias of neonatal T cells, with preferential differentiation toward short-lived pre-T effector cells. Remarkably, adjuvantation with CpG-ODNs redirect neonatal pre-T cells toward committed GC-T cells, as illustrated by increased expression of T signature genes and reduced expression of TH2-related genes.
MeSH Terms
- Adaptive Immunity
- Adjuvants, Immunologic
- Aging
- Animals
- Animals, Newborn
- Germinal Center
- Immunity, Innate
- Interleukin-13
- Lymphopoiesis
- Mice, Inbred C57BL
- T-Lymphocytes, Helper-Inducer
- Th2 Cells
- Transcriptome
Keywords
- T follicular helper cells
- adjuvant
- neonates
- transcriptional profile analysis
- vaccines
With reduced thymic activity, the population of naïve T cells in humans is maintained by homeostatic proliferation throughout adult life. In young adults, naïve CD4 T cells have enormous proliferative potential and plasticity to differentiate into different lineages. Here, we explored whether naïve CD4 T-cell aging is associated with a partial loss of this unbiased multipotency. We find that naïve CD4 T cells from older individuals have developed a propensity to develop into TH9 cells. Two major mechanisms contribute to this predisposition. First, responsiveness to transforming growth factor β (TGFβ) stimulation is enhanced with age due to an upregulation of the TGFβR3 receptor that results in increased expression of the transcription factor PU.1. Secondly, aged naïve CD4 T cells display altered transcription factor profiles in response to T-cell receptor stimulation, including enhanced expression of BATF and IRF4 and reduced expression of ID3 and BCL6. These transcription factors are involved in TH9 differentiation as well as IL9 transcription suggesting that the aging-associated changes in the transcription factor profile favor TH9 commitment.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Basic-Leucine Zipper Transcription Factors
- Blood Donors
- CD4-Positive T-Lymphocytes
- Cell Differentiation
- Female
- HEK293 Cells
- Healthy Volunteers
- Humans
- Inhibitor of Differentiation Proteins
- Interferon Regulatory Factors
- Interleukin-9
- Male
- Middle Aged
- Neoplasm Proteins
- Proteoglycans
- Proto-Oncogene Proteins
- Proto-Oncogene Proteins c-bcl-6
- Receptors, Antigen, T-Cell
- Receptors, Transforming Growth Factor beta
- T-Lymphocytes, Helper-Inducer
- Trans-Activators
- Transfection
- Young Adult
Keywords
- T-cell lineage differentiation
- aging
- immunosenescence
- interleukin 9
- multipotency
- transforming growth factor β
We report the development of squamous cell carcinomas (SCCs) of the skin at or near the site of ear tags composed of a nickel-copper alloy and used for identification during the course of a long-term study of incipient congenic FVB/N mice containing the human BCL6 transgene (FVB.Cg-Tg[tetO-BCL6]Bbn Tg[EmicroSR-tTa]83Bop), their littermate controls, and wild-type FVB/N. Of a total population of 160 mice, 14 (8.8%) developed SCCs in the tagged (right) ear after a median observation period of 25 months, but none of the animals developed tumors in the opposite ear (P = 0.0001). Nine of the fourteen mice with SCCs had to be euthanized because they were thought to be in distress from the ear condition, but the remaining five died or were euthanized for other reasons related to the research study. These animals ranged in age from 331 to 921 days at the time of death. Five of the tumors were well-differentiated (grade 1) SCCs; the remainder were grade 3 and tended to be deeply invasive neoplasms with undifferentiated areas containing a spindle cell component. One of these metastasized to kidney. When using the FVB/N mouse strain for long-term studies, it is necessary to consider that nearly 9% of the population may develop SCCs at or near ear-tag sites that may necessitate early removal of the animal.
MeSH Terms
- Aging
- Alloys
- Animal Identification Systems
- Animals
- Carcinoma, Squamous Cell
- Copper
- Ear, External
- Mice
- Mice, Inbred Strains
- Mice, Transgenic
- Nickel
- Skin Neoplasms
As can be seen from the above descriptions, the presentations at the CABM symposium provided an extraordinarily rich and diverse panorama of some of the most exciting science in current molecular biology. The presentations provided both a general overview and a detailed analysis of multiple biological systems, which despite their specific differences, also generated insights into important common themes. The success of any meeting is most appropriately measured by the kinds of questions that are provoked for future study, not merely by the recitation of past discoveries. In fact, the different presentations often raised highly similar questions for future study. At the most fundamental levels of transcriptional regulation, what are the signals that provide specificity of gene expression? What is the structural basis of specific protein-protein interactions, such as those between homeodomain proteins and beta-catenin-Lef1 interactions, and how are these determinants altered in transcriptional regulation in oncogenesis and in genetic diseases? How is specificity achieved in transcriptional repression, given that the fundamental biochemical reactions often involve modifications of relatively ubiquitous components such as histones? To what extent do changes in specificity of gene activation and repression or in chromosomal architecture mediate the kinds of developmental and oncogenic signals mediated through transcriptional regulators such as Myc, BCL6 and other basic helix-loop-helix proteins and the HMGI proteins? How do altered signaling pathways affect diseases of development and differentiation such as cardiovascular disorders and aging itself? What are the pathways that integrate extracellular signals and transcription during the process of organogenesis? How do fundamental cellular structures such as adhesion junctions, and the interactions of a cell with other cells and extracellular matrix impact on normal and abnormal development and on malignancy, and how do these levels of structure and function alter nuclear regulation of transcription and cell division? These are some of the recurrent questions raised in talk after talk at this symposium, questions that undoubtedly will provide the impetus for important discoveries that will be presented at future CABM symposia.
MeSH Terms
- Aging
- Animals
- Chromatin
- DNA-Binding Proteins
- Gene Expression Regulation
- Genes, myc
- Genetic Diseases, Inborn
- Growth
- Heart Diseases
- Homeodomain Proteins
- Humans
- Neoplasms
- Pre-B-Cell Leukemia Transcription Factor 1
- Proto-Oncogene Proteins
- Templates, Genetic
- Transcription Factors
- Transcription, Genetic
- Transcriptional Activation