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BACH transcription factors in innate and adaptive immunity

Key Points

  • BTB and CNC homology (BACH) proteins are transcriptional repressors of the basic region leucine zipper (bZIP) transcription factor family.

  • BACH proteins have widespread roles in immunological processes, including tolerance, memory, immunosuppression and iron homeostasis.

  • BACH proteins stabilize lineage commitment and promote cell-type-specific functions through the repression of alternative lineage programmes.

  • Competitive interactions with transcriptional activators of the bZIP family form a common mechanistic theme underlying the diverse functions of BACH factors.

  • The expression and function of BACH factors are regulated by extrinsic signals to enable fine-tuning of cellular functions.

Abstract

BTB and CNC homology (BACH) proteins are transcriptional repressors of the basic region leucine zipper (bZIP) transcription factor family. Recent studies indicate widespread roles of BACH proteins in controlling the development and function of the innate and adaptive immune systems, including the differentiation of effector and memory cells of the B and T cell lineages, CD4+ regulatory T cells and macrophages. Here, we emphasize similarities at a molecular level in the cell-type-specific activities of BACH factors, proposing that competitive interactions of BACH proteins with transcriptional activators of the bZIP family form a common mechanistic theme underlying their diverse actions. The findings contribute to a general understanding of how transcriptional repressors shape lineage commitment and cell-type-specific functions through repression of alternative lineage programmes.

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Figure 1: BACH proteins belong to the bZIP dimeric transcription factor family.
Figure 2: Repressor–activator relationships of BACH family transcription factors.
Figure 3: Functions of BACH factors in myeloid differentiation.
Figure 4: BACH2 restrains immune activation by controlling CD4+ T cell differentiation.
Figure 5: BACH2 restrains terminal effector programmes to promote memory CD8+ T cell differentiation.
Figure 6: BACH2 promotes B cell proliferation and memory cell differentiation.

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Acknowledgements

R.R is supported by the Wellcome Trust−Royal Society (grant 105663/Z/14/Z), the UK Biotechnology and Biological Sciences Research Council (grant BB/N007794/1) and Cancer Research UK (grant C52623/A22597). K.I. is supported by grants-in-aid (16K15227, 15H02506, 23116003) from the Japan Society for the Promotion of Science, and AMED-CREST and P-CREATE from the Japan Agency for Medical Research and Development. T.K. is supported by grants-in-aid (A212290070, A262213060) from the Japan Society for the Promotion of Science, and CREST (J098501018) from Japan Science Technology. The authors thank N. P. Restifo, L. Gattinoni, M. Stammers, A. Muto, K. Ochiai, A. Itoh-Nakadai, M. Watanabe-Matsui, D. Clever, R. Eil, F. M. Grant, R. Nasrallah, F. Sadiyah, T. M. Lozano, K. Okkenhaug, M. Turner and G. W. Butcher for ideas and discussion.

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Glossary

TPA response elements

(TREs). DNA sequences (with similarity to 5′-TGA(G/C)TCA-3′) that promote gene expression induced by the phorbol ester 12-O-tetradecanoylphorbol- 13-acetate (TPA) and that are the canonical recognition sequence of the activator protein 1 (AP-1) transcription factor complexes formed by dimers of JUN and FOS.

cAMP response elements

(CREs). DNA sequences (with similarity to 5′-TGACGTCA-3′) that promote gene expression induced by the cyclic AMP (cAMP) pathway and that are the canonical recognition sequence of CRE-binding protein (CREB) complexes.

Enhancers

Regulatory elements that function together with promoters to control gene expression. Enhancers can lie within intronic and intergenic regions and form looping interactions to bring enhancer-bound transcription factor complexes into contact with general transcription factors assembled at promoters. Distinct repertoires of enhancers function in different cell types, allowing for cell-type-specific regulation of gene expression.

Genetic polymorphisms

Genetic variations occurring in a specific population at such a frequency that the rarest of them cannot be maintained by recurrent mutation or immigration alone: therefore, they most frequently occur through inheritance.

Thymus-derived Treg cells

(tTreg cells). Most of these cells develop at the CD4+ single-positive stage of thymic T cell maturation as a result of the intermediate affinity of their T cell receptors for self-antigens. These cells contribute to peripheral tolerance against self-antigens.

Peripherally derived Treg cells

(pTreg cells). These cells develop from mature CD4+FOXP3 T cells in peripheral tissues. pTreg cells are frequently induced at mucosal sites, such as the lungs and gut, where they contribute to tolerance against innocuous foreign antigens.

Progressive differentiation model

Proposes that naive T cells differentiate into a heterogeneous pool of memory precursor and effector T cells early during infection. Effector cells are short-lived and die following the withdrawal of antigen. Memory precursor cells survive after contraction of the effector population and give rise to memory cells. The alternative linear differentiation model proposes that naive CD8+ T cells differentiate uniformly into effector cells early during immune responses, and a subset of these differentiate into memory cells on the withdrawal of antigen.

Cellular senescence

A form of irreversible growth arrest that limits the replicative lifespan of cells. Replicative senescence is induced by telomere shortening that occurs as a result of DNA replication during mitosis. Premature cellular senescence occurs in the absence of telomere shortening and results in growth arrest and apoptosis through the action of gene products of the INK4/ARF locus.

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Igarashi, K., Kurosaki, T. & Roychoudhuri, R. BACH transcription factors in innate and adaptive immunity. Nat Rev Immunol 17, 437–450 (2017). https://doi.org/10.1038/nri.2017.26

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