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.

Figure 1

Bcl-6 and Blimp-1 are reciprocally antagonistic transcription factors. Mechanisms of Bcl-6 and Blimp-1 antagonism and their broad influences on lymphocyte differentiation and function. CTL, cytotoxic T lymphocyte.

Figure 2

Roles of Bcl-6 and Blimp-1 in B cell differentiation. Bcl-6 and Blimp-1 are required at various steps of B cell differentiation (as indicated by arrow labels).

Figure 3

Roles of Bcl-6 and Blimp-1 in T cell differentiation. (a,b) Two proposed models of effector CD4⁺ T cell differentiation: model 1 (a) and model 2 (b). in b, the partial T_H1, T_H2, T_reg and T_H17 characteristics of T_FH cells are not shown, for simplicity. (c) A model of CD8⁺ T cell effector and memory differentiation highlighting the similarities to CD4⁺ T cells. Dotted lines and question marks indicate uncertainty. +Ag, antigen stimulation; SLeC, short-lived effector cell; MPeC, memory precursor effector cell.

Figure 4

Functional effects of different amounts of Bcl-6 and Blimp-1 expression. The amount of Bcl-6 and Blimp-1 expression is balanced differently in different lymphocytes at distinct differentiation stages. Lymphocytes with higher expression of Bcl-6 exhibit greater proliferative capacity but less secretory capacity. Lymphocytes with higher expression of Blimp-1 exhibit lower proliferative capacity and greater secretory capacity. Although exhausted CD8⁺ T cells have large amounts of Blimp-1 and lower proliferative capacity, they do not have more secreted effectors. T_CM, central memory T cell; T_EM, effector memory T cell.