A role for Blimp1 in the transcriptional network controlling natural killer cell maturation

Abstract

IntroductionNatural killer (NK) cells are innate lymphocytes specialized in cytokine production and cytotoxicity toward tumors and virusinfected cells. NK cells develop in the bone marrow from hematopoietic stem cells (HSCs) via lymphoid precursors. 1 The earliest committed NK-cell precursors can be isolated from lineage marker-negative fetal thymus or adult bone marrow and express high levels of the interleukin 15 (IL-15)/interleukin 2 receptor␤ (IL-2R␤) chain (CD122 2 ). NK-cell precursors then undergo maturation and functional diversification in the bone marrow, thymus, and a variety of peripheral organs including the liver, spleen, and lymph nodes. 1 In the mouse, peripheral maturation in the spleen is characterized by the up-regulation of the markers CD43, Mac-1 (CD11b), CD94, and KLRG1, with concomitant down-regulation of CD27 and ckit. 1,[3][4][5][6] Mature Mac-1 high KLRG1 ϩ CD27 low NK cells are the dominant population in nonlymphoid organs (with the exception of the liver). 3,7 In contrast to B and T cells, knowledge about the transcriptional circuitries controlling NK-cell development and maturation remains limited. Several factors, including E4BP4, 8,9 Tox, 10 and Id2, 11 are required for the development of NK cells from early progenitors, whereas GATA3 is essential for thymic NK cells 12 and modulates the function of mature NK cells. 13 A second group of transcription factors, including Ets1, 14 E74-like factor 4, 15 interferon regulatory factor 2 (IRF2), 16 and T-bet, 17,18 is more specifically required for the later stages of NK-cell differentiation and function. Interestingly, a number of these factors, including Id2 and T-bet, also have important functions in CD8 ϩ T-cell differentiation. 19,20 Blimp1 (also known as Prdm1) is a pleiotropic transcription factor that plays crucial roles in the differentiation of plasma cells and CD8 ϩ effector T cells. [21][22][23][24][25] In both processes, Blimp1 is required for terminal differentiation and Blimp1 deficiency leads to loss of functional antibody-secreting cells and short-lived cytotoxic T cells. Moreover, in CD8 ϩ T cells, Blimp1 is required for the optimal expression of cytotoxic molecules such as granzyme B and perforin and for the regulation of chemokine receptors such as CC-chemokine receptor 7 (CCR7), CCR5, and CCR6, but is dispensable for most cytokine production. 24,25 Blimp1 is also broadly required for the maintenance of T-cell homeostasis, because mice that lack Blimp1 in all T cells or mice reconstituted with Blimp1-deficient fetal liver cells show an accumulation of activated T cells and develop immunopathology. 22,26 In CD4 ϩ T cells, Blimp1 has been suggested to attenuate Th1 differentiation by repressing the genes encoding T-bet and interferon␥ (IFN␥). 27 Blimp1 expression within B and T cells is controlled by 2 transcription factors, IRF4 and Bcl6. While Bcl6 and Blimp1 mutually repress the expression of each other in activated B and CD4 ϩ T cells, 28 IRF4 directly activates Blimp1 expression. 29 We show that Blimp1 is expressed ...

Transcription Factor Runx3 Regulates Interleukin-15-Dependent Natural Killer Cell Activation

“…7B and C). Among these genes, Prdm1 (Blimp1), Kit, and Tnfrsf9 are of special interest, since their expression is induced by IL-15 and they are known to be involved in NKC proliferation (57)(58)(59). Expression of Prdm1 was upregulated in Runx3 (Fig.…”

Identification and expression profiles of prdm1 in medaka Oryzias latipes

“…Prdm1-induced maturation of lymphocytes is correlated with the ability of Prdm1 to repress numbers of genes critical for mature B cell identity and cellular proliferation [5,[8][9][10][11][12][13]. Prdm1 is also needed for the activation of T cells [14][15][16][17][18], the differentiation of myeloid lineage [19] and the maturation of nature killer (NK) cells [20].…”

Activation of the Hippo pathway by CTLA-4 regulates the expression of Blimp-1 in the CD8+T cell

“…These loss-of-function studies (4,5) indicate that Blimp-1 is required for terminal differentiation by the activated CD8 + T cell, which it for two other lymphocytic lineages, the B (8) and NK (9) cells. T-bet promotes Blimp-1 expression in the natural killer (NK) cell (9), and a similar role may be expected in the CD8 + cell, because T-bet-(2) and Blimp-1-deficient (4, 5) CD8 + T cells have similar differentiation phenotypes. Moreover, in vitro studies have shown that T-bet expression enables signaling by the IL-2 receptor to induce Blimp-1 transcription (10).…”