DIFFERENTIATION AND IMMUNOLOGY

By D. NOTAY

CONTENTS GENETIC AND EPIGENETIC CONTROL OF EARLY LYMPHOCYTE DEVELOPMENT THE ROLE OF BTB-ZINC FINGER TRANSCRIPTION FACTORS DURING T CELL DEVELOPMENT AND IN THE REGULATION OF T CELL-MEDIATED IMMUNITY TRANSCRIPTIONAL CONTROL OF THE DEVELOPMENT AND FUNCTION OF VA14I NKT CELLS TRANSCRIPTIONAL CONTROL OF REGULATORY T CELLS T CELL DIFFERENTIATION TRANSCRIPTIONAL CONTROL OF NK CELL DIFFERENTIATION AND FUNCTION TRANSCRIPTIONAL CONTROL OF PRE-B CELL DEVELOPMENT AND LEUKEMIA PREVENTION TRANSCRIPTION FACTORS CONTROLLING INNATE LYMPHOID CELL FATE DECISIONS TRANSCRIPTIONAL CONTROL OF DENDRITIC CELL DIFFERENTIATION HELPER T CELL PLASTICITY: IMPACT OF EXTRINSIC AND INTRINSIC SIGNALS ON TRANSCRIPTOMES AND EPIGENOMES GENETIC AND EPIGENETIC CONTROL OF EARLY LYMPHOCYTE DEVELOPMENT ABSTRACT T, B, AND NK LYMPHOCYTES ARE GENERATED FROM PLURIPOTENT HEMATOPOIETIC STEM CELLS THROUGH A SUCCESSIVE SERIES OF LINEAGE RESTRICTION PROCESSES MANY REG- ULATORY COMPONENTS, SUCH AS TRANSCRIPTION FACTORS, CYTOKINES/CYTOKINE RECEPTORS, AND SIGNAL TRANSDUCTION MOLECULES ORCHESTRATE CELL FATE SPECI?CATION AND DETERMINATION IN PARTICULAR, TRANSCRIPTION FACTORS PLAY A KEY ROLE IN REGULATING LINEAGE-ASSOCIATED GENE PROGRAMS RECENT ?NDINGS SUGGEST THE INVOLVEMENT OF EPIGENETIC FACTORS IN THE MAINTENANCE OF CELL FATE HERE, WE REVIEW THE EARLY DEVELOPMENTAL EVENTS DURING LYMPHOCYTE LINEAGE DETERMINATION, FOCUSING ON THE TRANSCRIPTIONAL NETWORKS AND EPIGENETIC REGULATION FINALLY, WE ALSO DISCUSS THE DEVELOPMENTAL RELATIONSHIP BETWEEN ACQUIRED AND INNATE LYMPHOID CELLS INTRODUCTION GENERATION OF T AND B CELL PROGENITORS IN BM TRANSCRIPTIONAL REGULATION DURING T CELL LINEAGE COMMITMENT T AND MYELOID POTENTIAL ARE CLOSELY ASSOCIATED IN EARLY THYMIC PROGENITORS TERMINATION OF MYELOID POTENTIAL IN T CELL PROGENITORS TRANSCRIPTIONAL REGULATION THAT DETERMINES T CELL FATE TRANSCRIPTIONAL REGULATION OF B CELL LINEAGE COMMITMENT EPIGENETIC REGULATION IN LYMPHOCYTE DEVELOPMENT POLYCOMB GROUP PROTEINS AND LYMPHOID LINEAGE COMMITMENT DNA METHYLATION AND OTHER CHROMATIN MODIFIERS IN LYMPHOID CELL FATES TRANSCRIPTIONAL REGULATION OF ILC DEVELOPMENT AND THE RELATIONSHIP BETWEEN ACQUIRED AND INNATE LYMPHOCYTES CONCLUSIONS REFERENCES 1 INTRODUCTION LYMPHOCYTES CONSIST OF THE T AND B CELLS OF THE ADAPTIVE IMMUNE SYSTEM AS WELL AS NATURAL KILLER (NK) CELLS, LYMPHOID TISSUE INDUCING (LTI) CELLS, AND NATURAL HELPER (NH) CELLS, WHICH HAVE RECENTLY BEEN DE?NED AS A NEW SUBSET TERMED INNATE LYM- PHOID CELLS (ILCS) ALL OF THESE LYMPHOCYTES ARE DERIVED FROM HEMATOPOIETIC STEM CELLS (HSCS) FOUND IN FETAL LIVER BEFORE BIRTH AND IN BONE MARROW (BM) AFTER BIRTH, ALTHOUGH THE DEVELOPMENTAL PATHWAYS AND THE MOLECULAR MECHANISMS OF THEIR DIVERSI?CATION PROCESSES ARE STILL NOT COMPLETELY UNDERSTOOD THE LYMPHOCYTES ARE GENERATED THROUGH A GAIN OF SPECI?C GENE EXPRESSION SIGNATURES MEDIATED BY A COMBINATORIAL NETWORK OF TRANSCRIPTION FACTORS THIS IS ACCOMPANIED BY THE GRADUAL LOSS OF DIFFERENTIATION POTENTIAL FOR ALTERNATIVE CELL LINEAGES (YANG ET AL 2010; MANDEL AND GROSSCHEDL 2010) (FIG 1) LINEAGE-SPECI?C TRANSCRIPTION FACTORS PLAY PIVOTAL ROLES IN THE LINEAGE RESTRICTION PROCESS THESE TRANSCRIPTION FACTORS ACTIVATE LINEAGE-SPECI?C GENES TO PROMOTE LINEAGE DEVELOPMENT, WHILE SIMULTANEOUSLY RESTRICTING THE DEVELOPMENTAL POTENTIAL OF MULTIPOTENT PROGENITORS TO THE LYMPHOID PATHWAY BY SUPPRESSING THE LINEAGE-INAPPROPRIATE GENES, WHICH ARE ASSOCIATED WITH OTHER DIFFERENTIATION PATHWAYS RECENT ?NDINGS ALSO SUGGEST THAT THE DOWNREGULA- TION OF STEM CELL-ASSOCIATED GENES BY TRANSCRIPTION FACTORS IS ALSO IMPORTANT FOR LINEAGE RESTRICTION PROGRAMS (NUTT AND KEE 2007; ROTHENBERG ET AL 2008) MANY TRANSCRIPTION FACTORS HAVE BEEN SHOWN TO BE CRITICAL FOR THE GENERATION OF LYMPHOID CELLS HOWEVER, HOW THESE TRANSCRIPTION FACTORS WORK TOGETHER THROUGH REGULATORY NETWORKS AND HOW THE SPECI?C COMBINATIONS OF TRANSCRIPTION FACTORS WITHIN THE NETWORKS SYNERGIZE OR ANTAGONIZE EACH OTHER ARE YET TO BE DE?NED IN THIS REVIEW, WE FOCUS ON THE TRANSCRIPTIONAL NETWORKS AND THE EPIGENETIC MECHANISMS THAT ORCHESTRATE LYMPHOID CELL GENESIS AND PROVIDE AN OVERVIEW OF CURRENT MODELS OF THE LYMPHOID LINEAGE COMMITMENT PROCESS DURING IMMUNE CELL DEVELOPMENT 2 GENERATION OF T AND B CELL PROGENITORS IN BM MANY KINDS OF BM PROGENITORS INCLUDING HSCS AND THE DOWNSTREAM PROGENITORS WITH T OR B CELL POTENTIAL HAVE BEEN IDENTI?ED (FIG 1) THE EARLIEST PROGENITORS CAN BE ISOLATED BASED ON THE ABSENCE OF LINEAGE MARKERS (LIN-) IN COMBINATION WITH HIGH EXPRESSION OF C-KIT AND SCA-1 (LSK CELLS) (IKUTA AND WEISSMAN 1992; DIFFERENTIATION AND IMMUNOLOGY