Essential role for the transcription factor Bhlhe41 in regulating the development, self-renewal and BCR repertoire of B-1a cells

Kreslavsky, Taras; Vilagos, Bojan; Tagoh, Hiromi; Poliakova, Daniela Kostanova; Schwickert, Tanja A.; Wöhner, Miriam; Jaritz, Markus; Weiß, Siegfried; Taneja, Reshma; Rossner, Moritz J.; Busslinger, Meinrad

doi:10.1038/ni.3694

Cited by 97 publications

(155 citation statements)

References 67 publications

(100 reference statements)

Supporting

Mentioning

143

Contrasting

Order By: Relevance

“…In comparison to the other macrophage subsets in the kidney, CM2 upregulated several genes associated with tissue remodeling including MMP2, ADAMTS10 and HTRA1. The functions of several other genes preferentially expressed by CM2 are not well defined in macrophages; however, they did express BHLHE41, a gene that is also expressed in microglia and lung resident macrophage populations 17 , consistent with CM2 representing resident cells. Compared to CM2 cells from LD controls, lupus CM2 cells expressed higher levels of interferon stimulated genes, as well as anti-inflammatory genes (GRN, TMSB4X, CREB5) and inhibitors of TLR signaling (GIT2, TNFAIP8L2), and lower levels of proinflammatory genes (ALOX15B, WNT5A) (Supplementary Table 5) 17 .…”

Section: Classification and Annotation Of Myeloid Cell Clusters Reveamentioning

confidence: 74%

The immune cell landscape in kidneys of lupus nephritis patients

Arazi

Rao

Berthier

et al. 2018

Preprint

View full text Add to dashboard Cite

Lupus nephritis is a potentially fatal autoimmune disease, whose current treatment is ineffective and often toxic. To gain insights into disease mechanisms, we analyzed kidney samples from lupus nephritis patients and healthy controls using single-cell RNA-seq. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid, T, NK and B cells, demonstrating both pro-inflammatory and resolving responses. We found evidence of local activation of B cells correlated with an age-associated B cell signature, and of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, pointing to potential therapeutic targets. Gene expression of immune cells in urine and kidney was highly correlated, suggesting urine may be a surrogate for kidney biopsies. Our results provide a first comprehensive view of the complex network of leukocytes active in lupus nephritis kidneys.

show abstract

Section: Classification and Annotation Of Myeloid Cell Clusters Reveamentioning

confidence: 74%

The immune cell landscape in kidneys of lupus nephritis patients

Arazi

Rao

Berthier

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…Peak calling with a stringent P value of < 10 −10 identified 12,740 Bhlhe40‐binding regions, and assignment of the peaks to the nearest gene within a 50‐kb window defined 6,517 Bhlhe40 target genes (data not shown). De novo motif discovery identified the CACGTG version of the E‐box (Fig C) that we and others previously described as the Bhlhe40/Bhlhe41 binding motif (Jolma et al , ; Kreslavsky et al , ). Almost half of the Bhlhe40‐binding sites were observed within gene bodies, whereas only 28% of the binding sites were present in intergenic regions (Fig D).…”

Section: Resultsmentioning

confidence: 99%

“…We first identified the transcription factors Bhlhe41 and Bhlhe40 as regulators of the development and self‐renewal of fetal‐derived innate‐like B‐1a cells (Kreslavsky et al , ). The results reported here indicate that these factors are important regulators of another self‐renewing tissue‐resident leukocyte population—AMs.…”

Section: Discussionmentioning

confidence: 99%

“…While the Bhlhe40/Bhlhe41 deficiency resulted in a severe competitive disadvantage for both cell types in mixed BM chimeras, the functions of these factors in the two cell types are different. Bhlhe40/Bhlhe41‐deficient B‐1a cells exhibited impaired pro‐survival cytokine signaling due to downregulation of genes encoding subunits of IL‐5/IL‐3/GM‐CSF receptor family, including Csf2rb (Kreslavsky et al , ), while no such downregulation was observed in DKO AMs. On the contrary, while DKO B‐1a cells, despite reduced numbers, exhibited increased proliferation, the proliferation of DKO AMs was impaired, which likely contributed to their competitive disadvantage in chimeric mice.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Bhlhe40 and Bhlhe41 transcription factors regulate alveolar macrophage self‐renewal and identity

et al. 2019

Self Cite

View full text Add to dashboard Cite

Tissues in multicellular organisms are populated by resident macrophages, which perform both generic and tissue‐specific functions. The latter are induced by signals from the microenvironment and rely on unique tissue‐specific molecular programs requiring the combinatorial action of tissue‐specific and broadly expressed transcriptional regulators. Here, we identify the transcription factors Bhlhe40 and Bhlhe41 as novel regulators of alveolar macrophages (AMs)—a population that provides the first line of immune defense and executes homeostatic functions in lung alveoli. In the absence of these factors, AMs exhibited decreased proliferation that resulted in a severe disadvantage of knockout AMs in a competitive setting. Gene expression analyses revealed a broad cell‐intrinsic footprint of Bhlhe40/Bhlhe41 deficiency manifested by a downregulation of AM signature genes and induction of signature genes of other macrophage lineages. Genome‐wide characterization of Bhlhe40 DNA binding suggested that these transcription factors directly repress the expression of lineage‐inappropriate genes in AMs. Taken together, these results identify Bhlhe40 and Bhlhe41 as key regulators of AM self‐renewal and guardians of their identity.

show abstract

“…In other studies, the role of the transcription factors Bhlhe40 and Bhlhe41, in controlling late stages of B‐1a cell differentiation was established. B‐1a cells numbers were found highly reduced in Bhlhe40 –/– Bhlhe41 –/– mice when compared to their wild‐type counterparts . The experiments suggested that Bhlhe41 can repress the expression of cell cycle and BCR signaling regulators at the same time that allows pro‐survival cytokine signaling in these cells, thus promoting their self‐renewal …”

Section: B‐1 Lymphocytesmentioning

confidence: 96%

Innate-like B cell subsets during immune responses: Beyond antibody production

Romero‐Ramírez

Navarro-Hernandez

Cervantes‐Díaz

et al. 2018

Journal of Leukocyte Biology

View full text Add to dashboard Cite

B lymphocytes are recognized for their crucial role in the adaptive immunity since they represent the only leukocyte lineage capable of differentiating into Ab‐secreting cells. However, it has been demonstrated that these lymphocytes can exert several Ab‐independent functions, including engulfing and processing Ags for presentation to T cells, secreting soluble mediators, providing co‐stimulatory signals, and even participating in lymphoid tissues development. Beyond that, several reports claiming the existence of multiple B cell subsets contributing directly to innate immune responses have appeared. These “innate‐like” B lymphocytes, whose phenotype, development pathways, tissue distribution, and functions are in most cases notoriously different from those of conventional B cells, are crucial to early protective responses against pathogens by exerting “crossover” defensive strategies that blur the established boundaries of innate and adaptive branches of immunity. Examples of these mechanisms include the rapid secretion of the polyspecific natural Abs, increased susceptibility to innate receptors‐mediated activation, cytokine secretion, downstream priming of other innate cells, usage of specific variable immunoglobulin gene‐segments, and other features. As these new insights emerge, it is becoming preponderant to redefine the functionality of B cells beyond their classical adaptive‐immune tasks.

show abstract

Essential role for the transcription factor Bhlhe41 in regulating the development, self-renewal and BCR repertoire of B-1a cells

Cited by 97 publications

References 67 publications

The immune cell landscape in kidneys of lupus nephritis patients

The immune cell landscape in kidneys of lupus nephritis patients

Bhlhe40 and Bhlhe41 transcription factors regulate alveolar macrophage self‐renewal and identity

Innate-like B cell subsets during immune responses: Beyond antibody production

Contact Info

Product

Resources

About