Early growth response genes 2 and 3 regulate the expression of Bcl6 and differentiation of T follicular helper cells

T follicular helper (Tfh) cells support differentiation of B cells to plasma cells and high affinity antibody production in germinal centers (GC) and Tfh differentiation requires the function of B cell lymphoma 6 (Bcl6). We have now discovered that early growth response gene (Egr) 2 and 3 directly regulate the expression of Bcl6 in Tfh cells which is required for their function in regulation of GC formation. In the absence of Egr2 and 3, the expression of Bcl6 in Tfh cells is defective leading to impaired differentiation of Tfh cells resulting in a failure to form GCs following virus infection and defects in production of anti-viral antibodies. Enforced expression of Bcl6 in Egr2/3 deficient CD4 T cells partially restored Tfh differentiation and GC formation in response to virus infection. Our findings demonstrate a novel function of Egr2/3 which is important for Tfh cell development and Tfh cell mediated B cell immune responses.This work was supported by Arthritis Research UK. The authors declare that they have no conflicts of interest with the contents of this article

IKK-induced NF-kappa B1 p105 proteolysis is critical for B cell antibody responses to T cell-dependent antigen

The importance of IκB kinase (IKK)–induced proteolysis of NF-κB1 p105 in B cells was investigated using Nfkb1SSAA/SSAA mice, in which this NF-κB signaling pathway is blocked. Nfkb1SSAA mutation had no effect on the development and homeostasis of follicular mature (FM) B cells. However, analysis of mixed bone marrow chimeras revealed that Nfkb1SSAA/SSAA FM B cells were completely unable to mediate T cell–dependent antibody responses. Nfkb1SSAA mutation decreased B cell antigen receptor (BCR) activation of NF-κB in FM B cells, which selectively blocked BCR stimulation of cell survival and antigen-induced differentiation into plasmablasts and germinal center B cells due to reduced expression of Bcl-2 family proteins and IRF4, respectively. In contrast, the antigen-presenting function of FM B cells and their BCR-induced migration to the follicle T cell zone border, as well as their growth and proliferation after BCR stimulation, were not affected. All of the inhibitory effects of Nfkb1SSAA mutation on B cell functions were rescued by normalizing NF-κB activation genetically. Our study identifies critical B cell-intrinsic functions for IKK-induced NF-κB1 p105 proteolysis in the antigen-induced survival and differentiation of FM B cells, which are essential for T-dependent antibody responses

Estrategia para conservar las poblaciones de buitres del viejo mundo utilizando el enfoque de una salud

One Health brings the powerful interrelationship between human and wildlife health together with ecosystem health. The initial concept of One Health was formulated decades ago and focused on disease transfer from wildlife to human populations. More recently, the concept has been used to associate resilience to disease with the health of the ecosystem and resilience to environmental stressors. The need for a One Health approach is particularly evident in the plight of Old World vultures, which are facing a conservation crisis due to drastic reductions in populations across their entire range. Moreover, vulture conservation exemplifies many contemporary tenets of One Health; vultures are critical to a sustainable and resilient ecosystem, which in turn is essential for the socio-ecological health of human communities. In this review, we examine the complex factors contributing to the demise of Old World vulture populations, using the lens of One Health to conceptualize the primary drivers impacting the health and sustainability of these populations. The One Health concept provides the basis for the development of a framework that incorporates a multidimensional approach and includes human health, wildlife health, environmental and disease-related stressors, disease incidences, societal pressures, and environmental contaminants. Integrating societal needs with management aimed at maintaining healthy vulture populations is key for successfully using a One Health framework to optimize the health of human and wildlife populations and ensure ecosystem health.El enfoque ‘‘Una Salud’’ promueve una poderosa interrelacio´n entre la salud de los humanos y de la fauna salvaje asociados a la salud de los ecosistemas. El concepto inicial de Una Salud fue formulado de´cadas atra´s y se enfocaba en la transferencia de enfermedades de la fauna salvaje a las poblaciones humanas. Ma´s recientemente, el concepto ha sido usado para asociar la resiliencia a las enfermedades con la salud de los ecosistemas y la resiliencia a factores de estre´s ambiental. La necesidad de utilizar el enfoque de Una Salud es particularmente evidente ante la dif´ıcil situacio´n de los buitres del Viejo Mundo, los cuales se enfrentan a una situacio´n de crisis de conservacio´n debido a la reduccio´n dra´stica en sus poblaciones a lo largo de toda su a´rea de distribucio´n. Adema´s, la conservacio´n de los buitres ejemplifica mucho de los principios contempora´neos de Una Salud; los buitres son cr´ıticos para un ecosistema sostenible y resiliente, lo que a su vez es esencial para la salud socio-ecolo´gica de las comunidades humanas. En esta revisio´n, examinamos los factores complejos que contribuyen al descenso de las poblaciones de buitres del Viejo Mundo, usando el enfoque de Una Salud para conceptualizar los factores principales que impactan en la salud y la sostenibilidad de estas poblaciones. El concepto de Una Salud proporciona las bases para el desarrollo de un marco de referencia que incorpora un enfoque multidimensional, incluyendo la salud humana y de la vida silvestre, factores estresantes ambientales y de enfermedades, incidencia de enfermedades, presiones sociales y qu´ımicos ambientales. Integrar las necesidades de la sociedad con la gestio´n destinada a mantener poblaciones saludables de buitres es clave para usar exitosamente el marco de referencia de Una Salud y as´ı optimizar la salud de las poblaciones humanas y de la fauna salvaje asegurando la salud del ecosistema.The National Science Foundationhttps://bioone.org/journals/journal-of-raptor-researcham2022Zoology and Entomolog

Egr2 and 3 control adaptive immune responses by temporally uncoupling expansion from T cell differentiation

Egr2 and 3 are important for maintaining immune homeostasis. Here we define a fundamental function of Egr2 and 3 operating as a checkpoint that controls the transition between clonal expansion and differentiation of effector T cells. Egr2 and 3 deficiency resulted in defective clonal expansion, but hyper-activation and excessive differentiation of T cells in response to viral infection. Conversely, sustained Egr2 expression enhanced expansion, but severely impaired effector differentiation. Egr2 bound to and controlled the expression of genes regulating proliferation (Myc, Myb) and differentiation repressors (Bcl6, Id3), while repressing transcription factors required for effector function (Zeb2, RORa, RORc, Bhlhe40). Egr2 and 3 expression in T cells was regulated reciprocally by antigen and IFNγ providing a mechanism for adjusting proliferation and differentiation of individual T cells. Thus, Egr2 and 3 are upstream regulators of effector CD4 and CD8 T cells that are essential for optimal responses with limited immunopathology