Mina, an Il4 repressor, controls T helper type 2 bias

Abstract

T helper-2 (T H 2)-bias, the propensity of naive CD4 + T cells to differentiate into interleukin 4 (IL-4) secreting T H 2 cells, is a genetic trait impacting infectious, autoimmune and allergic disease susceptibility. T H 2-bias correlates with the amount of IL-4 initially secreted by newly activated T H cells that feeds back positively through the IL-4R-STAT6-GATA3 pathway to drive T H 2 development. Here, we identify Mina, a JmjC family member, as a genetic determinant of T H 2-bias. Mina specifically bound to and repressed the Il4 promoter. Mina overexpression in transgenic mice impaired Il4 expression, while its knockdown in primary CD4 + T cells led to Il4 derepression. Together, these findings provide mechanistic insight into an Il4 regulatory pathway controlling T H differentiation and genetic variation in T H 2-bias. Naive CD4 + T cells are multipotent sentinels of the immune system, poised to respond to instructive signals from antigen-presenting cells by differentiating into distinct effector cell lineages. These include T helper (T H ) 1 and T H 2 cells, differentially adapted for the control, respectively, of intra-and extracellular pathogens, in part via developmentally acquired potential for high expression of distinct cytokine genes 1 . Dysregulated CD4 + T cell development can promote susceptibility to infectious, autoimmune and allergic disease [2][3][4][5][6][7][8][9] .Interleukin 4 (IL-4) [http://www.signaling-gateway.org/molecule/query?afcsid=A001262], the canonical T H 2 effector cytokine, is also a critical developmental determinant, promoting Accession codesThe microarray data are deposited in RCAI RefDIC (URL: http://refdic.rcai.riken.jp/welcome.cgi) 50 under the following accession codes: RMSPTB007001 and RMSPTB008001. 11,12 to promote the differentiation of T H 2 cells possessing the capacity to secrete copious amounts of IL-4 10, 13-18 . Thus, regulation of autocrine IL-4 expression by activated T H cells is a key control point in T helper cell lineage commitment. Nonetheless, the molecular mechanism underlying this regulation is incompletely understood. Author contributions NIH Public AccessT H 2-bias is a complex genetic trait characterizing variation in the propensity of naive T H cells to differentiate into T H 2 (as opposed to T H 1) cells. T H 2-bias, measured experimentally as the amount of IL-4 produced by effector CD4 + T cells differentiated in vitro from naive T H cells activated under 'neutral' conditions (no exogenous cytokines added, except IL-2, and cultured without cytokine-specific antibodies), varies over 50-fold from the highproducer phenotype of BALB/c mice to the low-producer phenotype of B10.D2 mice and correlates with susceptibility to T H 2-dependent diseases such as bronchial asthma and leishmaniasis [14][15][16][19][20][21][22] . Various cellular mechanisms have been suggested as the basis for T H 2-bias, including variation in the sensitivity to prostaglandin 2 (PGE 2 )-dependent inhibition of interferon-γ (IFN-γ) production 23 , the timing of IL-1...

A SNP uncoupling Mina expression from the TGFβ signaling pathway

“…Developmentally, in the lung, Mina expression is low in neonatal mice and high in adults (Stephania Courmier, personal communication). In naïve T helper cells activated by PMA/ionomycin, Mina protein level peaked in the cytosol and the nucleus, respectively, at around 72 h (eightfold above basal) and 18 h (threefold above basal) 3. At the transcriptional level, TCR crosslinking of naïve CD4 T cells induced Mina mRNA level to rise approximately threefold over 24 h 3.…”

“…In naïve T helper cells activated by PMA/ionomycin, Mina protein level peaked in the cytosol and the nucleus, respectively, at around 72 h (eightfold above basal) and 18 h (threefold above basal) 3. At the transcriptional level, TCR crosslinking of naïve CD4 T cells induced Mina mRNA level to rise approximately threefold over 24 h 3. In order to build a framework for understanding how Mina gene expression is regulated we set out to explore the cis regulatory landscape of the Mina gene locus.…”

“…Although Mina expression is ubiquitous, its quantitative level varies across different cell types, developmental stages, and activation states 2, 3. For example, its expression is elevated in parts of the CNS, the testes, the eye, lymph nodes, the spleen, T helper cells and plasmacytoid dendritic cells.…”

“…Mina is a widely expressed pleiotropic protein with known oncogenic and immunoregulatory roles 1, 2, 3, 4, 5, 6, 7. Originally discovered as a Myc‐induced nuclear antigen of 53 kDa with pro‐proliferative activity in promyelocytic leukemia HL60 cells 1, it has subsequently been shown to be overexpressed in a wide variety of human cancers, in some cases providing prognostic value 2.…”

“…Originally discovered as a Myc‐induced nuclear antigen of 53 kDa with pro‐proliferative activity in promyelocytic leukemia HL60 cells 1, it has subsequently been shown to be overexpressed in a wide variety of human cancers, in some cases providing prognostic value 2. Independently, its encoding gene was mapped to a locus regulating Th2‐bias 3, 8, 9, a genetic trait defined as the propensity of naïve T helper cells to develop in vitro into IL4‐producing Th2 cells 9, 10 and it was shown to act as a dose‐dependent transcriptional corepressor of the gene encoding interleukin‐4 (IL4) 3, a key regulator of Th2 development 9, 10, 11, 12. Later work with Mina KO mice, however, revealed the dispensability of Mina for normal Th2 development, perhaps due to functional redundancy with its close evolutionary and structural paralog No66 13.…”