Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation

Abstract

Bcl-6 and Blimp-1 have recently been identified as key transcriptional regulators of effector and memory differentiation in CD4 + T cells and CD8 + T cells. Bcl-6 and Blimp-1 were previously known to be critical regulators of effector and memory differentiation of B lymphocytes. The new findings unexpectedly point to the Bcl-6 and Blimp-1 regulatory axis as a ubiquitous mechanism for controlling effector and memory lymphocyte differentiation and function. Bcl-6 and Blimp-1 are antagonistic transcription factors and can function as a self-reinforcing genetic switch for cell-fate decisions. However, their influences in different lymphocytes are complex. Here we review and examine the commonalities and differences in the functions of these transcription factors in CD4 + follicular helper T FH lymphocytes, effector CD8 + T lymphocytes and B lymphocytes. CD4 + T cells, CD8 + T cells and B cells are distinct lymphocyte populations with unique, critical roles in adaptive immunity. Each population has been thought to be controlled by quite different transcriptional regulation for its individual effector and memory differentiation programs 1 . Bcl-6 and Blimp-1 (encoded by Prdm1) are transcriptional repressors with the ability to block each other's expression (Fig. 1). The recent identification of central roles for Bcl-6 and Blimp-1 in the differentiation of follicular helper CD4 + T cells [2][3][4] and CD8 + T cell effector and memory differentiation processes [5][6][7] , combined with their well documented roles in B cells, has revealed an unexpected common system used in key fate decisions made by mature CD4 + T cells, CD8 + T cells and B cells. Bcl-6 and Blimp-1 in B cell differentiationBcl6 was first identified as a proto-oncogene frequently expressed in non-Hodgkin's lymphoma as a result of chromosomal translocations [8][9][10][11][12] . Bcl-6 protein was found to be highly expressed in germinal center B cells, which led to the conclusion that many B cell lymphomas begin as germinal center B cells that then acquire dysregulated Bcl-6 expression 11 . The germinal center reaction is the process by which antigen-specific B cells mature into the long-lived plasma cells (antibody-secreting cells) and memory B cells that constitute the cellular components of immunological memory for the B cell lineage 1,13 (Fig. 2). After activation and costimulation, B cells differentiate into either short-lived plasma cells or germinal center B cells 1,14 (Fig. 2).Correspondence should be addressed to S.C. (shane@liai.org). Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/. Short-lived plasma cells stop proliferating and elaborate a large secretory apparatus for producing antibodies to quickly combat infection 1,14 . In contrast, germinal center B cells have a minimal secretory apparatus and are instead specialized for proliferation and affinity maturation, the exquisitely complex process of rapidly evolving a B cell receptor of higher affinity for the production of high-a...

Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4

“…We could demonstrate that Bcl-6 binds and inhibits transcription from the CTLA-4 promoter, and, therefore, if T cells are activated in the presence of the MR, lack of Bcl-6 allows expression of CTLA-4. Bcl-6 is a key regulator in Th-cell differentiation and in the regulation of CD4 + and CD8 + T-cell memory (40). Although it has been demonstrated before that Bcl-6 is transiently expressed in activated T cells and continuously up-regulated in CD8 + effector T cells (41), its role in these cells is less understood.…”

Distinctive microRNA expression profiles in CD34+ bone marrow cells from patients with myelodysplastic syndrome

“…20 In MDS, we detected a negative association of the expression of another miR-127 target, proto-oncogene BCL6, 19 functioning also as a transcriptional regulator required for B-and T-lymphocyte terminal differentiation. 27 Thus, overexpression of miR-127 may be linked with the downregulation of genes involved in B-cell lineage differentiation previously seen in MDS. 11,28 In CD34+ cells of all MDS subtypes, we confirmed an upregulation of the miR-1/miR-133a cluster (Po0.05, see Supplementary Table 2), which was recently published by Hussein et al 9 In contrast to increased expression in MDS/AML, this miRNA cluster was downregulated in neutrophils from patients with polycythemia vera and essential trombocytosis, 29 indicating its different roles in myeloid neoplasms.…”

Control of the STAT6–BCL6 Antagonism by SWAP-70 Determines IgE Production

“…How STAT6 is targeted to the germline ε promoter and hence how specific switching to IgE is initiated is unknown. The effect of STAT6 on Iε is antagonized by BCL6 (10,11), a POZ/zinc-finger transcription factor with mostly repressor activity (12). BCL6 and STAT6 bind to a largely overlapping sequence within Iε.…”