Myor/ABF-1 Mrna Expression Marks Follicular Helper T Cells but Is Dispensable for Tfh Cell Differentiation and Function In Vivo

Follicular T helper cells (Tfh) are crucial for effective antibody responses and long term T cell-dependent humoral immunity. Although many studies are devoted to this novel T helper cell population, the molecular mechanisms governing Tfh cell differentiation have yet to be characterized. MyoR/ABF-1 is a basic helix-loop-helix transcription factor that plays a role in the differentiation of the skeletal muscle and Hodgkin lymphoma. Here we show that MyoR mRNA is progressively induced during the course of Tfh-like cell differentiation in vitro and is expressed in Tfh responding to Alum-precipitated antigens in vivo. This expression pattern suggests that MyoR could play a role in the differentiation and/or function of Tfh cells. We tested this hypothesis using MyoR-deficient mice and found this deficiency had no impact on Tfh differentiation. Hence, MyoR-deficient mice developed optimal T-dependent humoral responses to Alum-precipitated antigens. In conclusion, MyoR is a transcription factor selectively up-regulated in CD4 T cells during Tfh cell differentiation in vitro and upon response to alum-protein vaccines in vivo, but the functional significance of this up-regulation remains uncertain.

[1]  M. Kaplan,et al.  The Transcription Factor Twist1 Limits T Helper 17 and T Follicular Helper Cell Development by Repressing the Gene Encoding the Interleukin-6 Receptor α Chain* , 2013, The Journal of Biological Chemistry.

[2]  R. Ahmed,et al.  T‐cell memory differentiation: insights from transcriptional signatures and epigenetics , 2013, Immunology.

[3]  F. Andris,et al.  The capacity of Th2 lymphocytes to deliver B‐cell help requires expression of the transcription factor STAT3 , 2013, European journal of immunology.

[4]  S. Tangye,et al.  The good, the bad and the ugly — TFH cells in human health and disease , 2013, Nature Reviews Immunology.

[5]  Y. Matsuzaki,et al.  Basic helix-loop-helix transcriptional factor MyoR regulates BMP-7 in acute kidney injury. , 2013, American journal of physiology. Renal physiology.

[6]  J. Cannons,et al.  T follicular helper cell diversity and plasticity. , 2013, Trends in immunology.

[7]  W. Leonard,et al.  Interleukin-21 Is a Critical Cytokine for the Generation of Virus-Specific Long-Lived Plasma Cells , 2013, Journal of Virology.

[8]  R. Ahmed,et al.  Distinct memory CD4+ T cells with commitment to T follicular helper- and T helper 1-cell lineages are generated after acute viral infection. , 2013, Immunity.

[9]  Joshua W. Vincentz,et al.  Twist1 Regulates Ifng Expression in Th1 Cells by Interfering with Runx3 Function , 2012, The Journal of Immunology.

[10]  S. Tangye,et al.  The origins, function, and regulation of T follicular helper cells , 2012, The Journal of experimental medicine.

[11]  Shane Crotty.  The 1‐1‐1 fallacy , 2012, Immunological reviews.

[12]  S. Crotty,et al.  Bcl6 and Maf Cooperate To Instruct Human Follicular Helper CD4 T Cell Differentiation , 2012, The Journal of Immunology.

[13]  A. Elkahloun,et al.  Functional and epigenetic studies reveal multistep differentiation and plasticity of in vitro-generated and in vivo-derived follicular T helper cells. , 2011, Immunity.

[14]  Julio E. Agno,et al.  Transforming Growth Factor β Receptor Type 1 Is Essential for Female Reproductive Tract Integrity and Function , 2011, PLoS genetics.

[15]  S. Crotty,et al.  ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. , 2011, Immunity.

[16]  Riitta Lahesmaa,et al.  Genomic views of STAT function in CD4+ T helper cell differentiation , 2011, Nature Reviews Immunology.

[17]  S. Crotty,et al.  Follicular helper CD4 T cells (TFH). , 2011, Annual review of immunology.

[18]  Burton E. Barnett,et al.  IL-21 and IL-6 Are Critical for Different Aspects of B Cell Immunity and Redundantly Induce Optimal Follicular Helper CD4 T Cell (Tfh) Differentiation , 2011, PloS one.

[19]  B. Kee,et al.  E proteins and the regulation of early lymphocyte development , 2010, Immunological reviews.

[20]  Jinfang Zhu.  Transcriptional regulation of Th2 cell differentiation , 2010, Immunology and cell biology.

[21]  K. Toellner,et al.  IL-21 regulates germinal center B cell differentiation and proliferation through a B cell–intrinsic mechanism , 2010, The Journal of experimental medicine.

[22]  Y. Wang,et al.  Dec2 Promotes Th2 Cell Differentiation by Enhancing IL-2R Signaling1 , 2009, The Journal of Immunology.

[23]  C. King,et al.  New insights into the differentiation and function of T follicular helper cells , 2009, Nature Reviews Immunology.

[24]  C. Mackay,et al.  The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. , 2009, Immunity.

[25]  Burton E. Barnett,et al.  Bcl6 and Blimp-1 Are Reciprocal and Antagonistic Regulators of T Follicular Helper Cell Differentiation , 2009, Science.

[26]  R. Nurieva,et al.  Bcl6 Mediates the Development of T Follicular Helper Cells , 2009, Science.

[27]  W. Leonard,et al.  Interleukin-6/STAT3 signaling regulates the ability of naive T cells to acquire B-cell help capacities. , 2009, Blood.

[28]  V. Kuchroo,et al.  The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells , 2009, Nature Immunology.

[29]  C. Loddenkemper,et al.  Autoregulation of Th1-mediated inflammation by twist1 , 2008, The Journal of experimental medicine.

[30]  C. Mackay,et al.  A fundamental role for interleukin-21 in the generation of T follicular helper cells. , 2008, Immunity.

[31]  D. Hwang,et al.  Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. , 2008, Immunity.

[32]  Lai Wei,et al.  IL-21 Is Produced by Th17 Cells and Drives IL-17 Production in a STAT3-dependent Manner* , 2007, Journal of Biological Chemistry.

[33]  J. Cyster,et al.  Role of CXCR5 and CCR7 in Follicular Th Cell Positioning and Appearance of a Programmed Cell Death Gene-1High Germinal Center-Associated Subpopulation1 , 2007, The Journal of Immunology.

[34]  H. Rahn,et al.  Follicular B helper T cell activity is confined to CXCR5hiICOShi CD4 T cells and is independent of CD57 expression , 2006, European journal of immunology.

[35]  F. Andris,et al.  CD4+CD25+ regulatory T cells control the magnitude ofT‐dependent humoral immune responses to exogenous antigens , 2006, European journal of immunology.

[36]  H. Stein,et al.  Intrinsic inhibition of transcription factor E2A by HLH proteins ABF-1 and Id2 mediates reprogramming of neoplastic B cells in Hodgkin lymphoma , 2006, Nature Immunology.

[37]  C. Murre.  Helix-loop-helix proteins and lymphocyte development , 2005, Nature Immunology.

[38]  H. Okano,et al.  Musculin/MyoR is expressed in kidney side population cells and can regulate their function , 2005, The Journal of cell biology.

[39]  C. Mackay,et al.  T Follicular Helper Cells Express a Distinctive Transcriptional Profile, Reflecting Their Role as Non-Th1/Th2 Effector Cells That Provide Help for B Cells1 , 2004, The Journal of Immunology.

[40]  R. Flavell,et al.  Kinetic analysis of genomewide gene expression reveals molecule circuitries that control T cell activation and Th1/2 differentiation. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[41]  S. Szabo,et al.  Molecular mechanisms regulating Th1 immune responses. , 2003, Annual review of immunology.

[42]  P. McCormick,et al.  MyoR is expressed in nonmyogenic cells and can inhibit their differentiation. , 2003, Experimental cell research.

[43]  Andrea Califano,et al.  Identification of Hodgkin and Reed-Sternberg cell-specific genes by gene expression profiling. , 2003, The Journal of clinical investigation.

[44]  E. Olson,et al.  Control of Facial Muscle Development by MyoR and Capsulin , 2002, Science.

[45]  A. Sher,et al.  A Critical Role for IL-21 in Regulating Immunoglobulin Production , 2002, Science.

[46]  P. Loetscher,et al.  Cxc Chemokine Receptor 5 Expression Defines Follicular Homing T Cells with B Cell Helper Function , 2000, The Journal of experimental medicine.

[47]  R. Barndt,et al.  Functions of E2A-HEB Heterodimers in T-Cell Development Revealed by a Dominant Negative Mutation of HEB , 2000, Molecular and Cellular Biology.

[48]  L. Glimcher,et al.  Lineage commitment in the immune system: the T helper lymphocyte grows up. , 2000, Genes & development.

[49]  Laurie H Glimcher,et al.  A Novel Transcription Factor, T-bet, Directs Th1 Lineage Commitment , 2000, Cell.

[50]  C. Murre,et al.  Helix-Loop-Helix Proteins: Regulators of Transcription in Eucaryotic Organisms , 2000, Molecular and Cellular Biology.

[51]  C. Murre,et al.  Thymocyte Maturation Is Regulated by the Activity of the Helix-Loop-Helix Protein, E47 , 1999, The Journal of experimental medicine.

[52]  E. Olson,et al.  MyoR: a muscle-restricted basic helix-loop-helix transcription factor that antagonizes the actions of MyoD. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[53]  C. Begley,et al.  musculin: a murine basic helix-loop-helix transcription factor gene expressed in embryonic skeletal muscle , 1998, Mechanisms of Development.

[54]  J. V. van Dongen,et al.  Characterization of ABF-1, a Novel Basic Helix-Loop-Helix Transcription Factor Expressed in Activated B Lymphocytes , 1998, Molecular and Cellular Biology.

[55]  D. Pinkel,et al.  E2A deficiency leads to abnormalities in alphabeta T-cell development and to rapid development of T-cell lymphomas , 1997, Molecular and cellular biology.

[56]  M. Kaplan,et al.  Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. , 1996, Immunity.

[57]  D. Littman,et al.  A heterodimer of HEB and an E12-related protein interacts with the CD4 enhancer and regulates its activity in T-cell lines , 1993, Molecular and cellular biology.

[58]  C. Murre,et al.  Localization of E2A mRNA expression in developing and adult rat tissues. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[59]  W. Leonard,et al.  The Dectin-2 family of C-type lectin-like receptors: an update , 2013, International immunology.

[60]  D. Littman,et al.  The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. , 2006, Cell.