title: Regulation of effector function of CNS autoreactive CD4 T cells through inhibitory receptors and IL-7Rα.
abstract: Multiple sclerosis (MS) is a chronic CNS autoimmune disease characterized by inflammation, demyelination, and neuronal degeneration, where myelin-specific CD4 T cells play critical roles in the formation of acute MS lesions and disease progression. The suppression of IL-7Rα expression and the upregulation of inhibitory receptors (PD-1, etc.) are essential parts of the cell-intrinsic immunosuppressive program regulating T effector functions to prevent autoimmunity. However, little is known on the factors regulating IL-7Rα/PD-1 balance in myelin-specific CD4 T effector/memory cells during the development of CNS autoimmunity.
  
  
  
  We analyzed the roles of the transcription factor T-bet in regulating the expression of IL-7Rα and inhibitory receptors in myelin-specific CD4 T cells. Furthermore, we compared the effects of different inflammatory cytokines that are crucial for Th1 and Th17 development in regulating the IL-7Rα/PD-1 balance.
  
  
  
  We discovered that T-bet suppresses the expression of inhibitory receptors (PD-1 and LAG-3) and promotes IL-7Rα expression in myelin-specific CD4 T cells in vitro and in vivo. As a result, T-bet skews IL-7Rα/PD-1 balance towards IL-7Rα and promotes enhanced effector function. Furthermore, IL-12 enhances IL-7Rα expression in a T-bet independent manner in myelin-specific Th1 cells. Meanwhile, IL-6, the cytokine inducing highly encephalitogenic Th17 differentiation, suppresses PD-1 while upregulating IL-7Rα, skewing IL-7Rα/PD-1 balance towards IL-7Rα, and promoting enhanced effector function. Moreover, blocking IL-7 signaling in myelin-specific CD4 T cells by αIL-7Rα significantly delays experimental autoimmune encephalomyelitis (EAE) onset and reduces disease severity.
  
  
  
  T-bet is a major transcription factor regulating IL-7Rα/PD-1 balance in myelin-specific CD4 T cells during EAE development, and there is a positive correlation between several major determinants promoting T cell encephalitogenicity (T-bet, IL-6, IL-12) and an IL-7Rα/PD-1 balance skewed towards IL-7Rα. Furthermore, IL-7 signaling inhibits PD-1 expression in myelin-specific CD4 T cells and blocking IL-7 signaling suppresses T cell encephalitogenicity. Therefore, interference with inhibitory pathways and IL-7Rα expression may suppress the encephalitogenic potential of myelin-specific CD4 T cells and have therapeutic benefits for MS patients.
authors.affiliation: Postbacculaureate Research Education Program, The Ohio State University, Columbus, OH, USA.
authors.forename: Patrick K
authors.initials: PK
authors.lastname: Nuro-Gyina
authors.affiliation: Neuroscience program, College of Arts and Sciences, The Ohio State University, Columbus, OH, USA.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Rieser
authors.affiliation: Neuroscience program, College of Arts and Sciences, The Ohio State University, Columbus, OH, USA.
authors.forename: Marissa C
authors.initials: MC
authors.lastname: Granitto
authors.affiliation: Department of Neurology, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Pei
authors.affiliation: Department of Microbial Infection and Immunity, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Molecular Cellular and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH, USA.
authors.forename: Priscilla W
authors.initials: PW
authors.lastname: Lee
authors.affiliation: Department of Neurology, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Saba
authors.initials: S
authors.lastname: Aqel
authors.affiliation: Department of Microbial Infection and Immunity, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Microbial Infection and Immunity, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.|Department of Neuroscience, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Lovett-Racke
authors.affiliation: Department of Neurology, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.|Department of Neuroscience, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Racke
authors.affiliation: Department of Neurology, Wexner Medical Center, The Ohio State University, Columbus, OH, USA. yuhong.yang@osumc.edu.|Department of Neurology, Wexner Medical Center, Biomedical Research Tower, The Ohio State University, 460 W 12th Ave, Room 0604, Columbus, OH, 43210, USA. yuhong.yang@osumc.edu.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002490:Central Nervous System / Q000276:immunology / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology* / Q000601:surgery*; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology / Q000633:toxicity; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics; D010446:Peptide Fragments / Q000276:immunology / Q000633:toxicity; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics; D053722:Receptors, Interleukin-17 / Q000378:metabolism*; D018417:Th1 Cells / Q000378:metabolism
chemical_list: D016207:Cytokines; C486765:Dner protein, mouse; C491673:Il17ra protein, mouse; D063308:Myelin-Oligodendrocyte Glycoprotein; D009419:Nerve Tissue Proteins; C491383:Pdcd1 protein, mouse; D010446:Peptide Fragments; D061026:Programmed Cell Death 1 Receptor; D011956:Receptors, Cell Surface; D053722:Receptors, Interleukin-17; C445081:myelin oligodendrocyte glycoprotein (35-55)
keywords: Experimental autoimmune encephalomyelitis (EAE); Inhibitory receptors; Multiple sclerosis (MS); T cell encephalitogenicity; Transcription factors