Short Introduction of c-Maf
c-Maf is a member of the basic leucine zipper transcription factors belonging to the AP-1 family. It has been shown that c-Maf is overexpressed in multiple myeloma (MM), enhancing tumor-stroma interactions. In the monocyte/macrophage lineage, c-Maf is essential for macrophage self-renewal.
Fig.1 Structures of the human Maf family proteins and the c-Jun bZIP transcription factor. (Imbratta, 2020)
c-Maf and γδ T Cell
Maf deficiency caused an absolute lineage block at the immature CD24+CD45RBlo γδ thymocyte stage. c-Maf enforced Tγδ17 cell identity by promoting chromatin accessibility and expression of key type 17 program genes, notably Rorc and Blk, while antagonizing the transcription factor TCF1, which promotes interferon-γ-producing γδ T cells (Tγδ1 cells). Furthermore, γδ T cell antigen receptor (γδ TCR) signal strength tuned c-Maf expression. c-Maf is considered a universal regulator of Tγδ17 cell differentiation and maintenance.
c-Maf in T Cells
c-Maf expression and activity are regulated at transcriptional, post-transcriptional, as well as post-translational levels. Transcription factors and RNA-mediated silencing control the amount of Maf transcripts, while phosphorylation will modify the activity, subcellular localization, and half-life of the protein.
In T cells, antigenic stimuli that modulate the stability of the c-Maf encoding mRNAs and/or the c-Maf protein may also induce the expression of transcriptional activators, or may cooperate with independent transcriptional stimuli, such as cytokine-driven STAT factors to induce c-Maf transcription. The selective use of those pathways by different stimuli and in distinct cell populations provides the potential for tailoring c-Maf expression to different circumstances.
Role of c-Maf in Tumor-Infiltrating CD8 T Cells
c-Maf is not expressed in CD8 T cells at a steady state. The expression of c-Maf in CD8 T cells was first described in tumor-infiltrating lymphocytes (TILs) obtained from a mouse melanoma model and melanoma patient.
Overexpression of c-Maf in CD8 T cells leads to a strong repression of IFN-γ and IL-2 production, and an increased expression of genes associated with T cell exhaustion. A dysfunctional state of T cells observed during chronic infections or in tumor-infiltrating lymphocytes (TILs).
When c-Maf was knocked-out in tumor-specific CD8 T cells, those cells had a much higher capacity to restrain tumor growth through increased IFN-γ production and increased survival.
c-Maf and Disease
The combined upregulation of multiple type 2 cytokines by c-Maf transgenic T-cells correlates with disease attenuation in some, but not all, models of diabetes. In the model of spontaneous diabetes, c-Maf significantly inhibits disease. Because diabetes in this model is dependent on major histocompatibility complex (MHC) class II restricted CD4 T-cell effector function, disease inhibition is most likely a consequence of the c-Maf-mediated early shift in type 2 cytokines produced by antigen-specific CD4 cells. c-Maf had no significant direct effects on T-cell proliferation in vitro or peri-insulitis in vivo.
c-Maf and Cancer
- c-Maf is also highly expressed in over half of the angioimmunoblastic T-cell lymphomas (AITL). Transgenic overexpression of c-Maf in T cells regulates the same gene expression set as in plasma cells and induces T-cell lymphoma development in mice, therefore indicating that c-Maf is a bona fide oncogene contributing to the progression of hematological malignancies.
- c-Maf is also expressed by other cancers, such as renal or head and neck cancer. Its expression is not systematically correlated with a bad prognosis.
- Overexpression of c-Maf is a much more frequent oncogenic event in MM. Scientists detected significant levels of c-Maf expression in 50% of myeloma cell lines and myeloma cells (MC) purified from patient bone marrow samples. c-Maf overexpression in MM drives cyclin D2, integrin β7, and ARK5 expression and leads to proliferation, adhesion to bone marrow stromal cells, invasion, and migration of plasma cells.
Fig.2 The oncoprotein c-Maf and its transactivation targets in multiple myeloma. (Kienast, 2004)
Many proteins secreted by γδ T cells play an important role in immune regulation. To better understand and explore the role of these proteins, Creative Biolabs has a series of related services in terms of γδ T cell. If you have any questions, please contact us.
- Imbratta, C.;et al. c-MAF, a Swiss Army Knife for Tolerance in Lymphocytes. Frontiers in Immunology. 2020, 11.
- Kienast, J.; Berdel WE. c-Maf in multiple myeloma: an oncogene enhancing tumor-stroma interactions. Cancer Cell. 2004, 5(2): 109-110.