Regulation of effector function of CNS autoreactive CD4 T cells through inhibitory receptors and IL-7Rα

Patrick K Nuro-Gyina; Elizabeth L Rieser; Marissa C Granitto; Wei Pei; Yue Liu; Priscilla W Lee; Saba Aqel; Jian Zhang; Amy E Lovett-Racke; Michael K Racke; Yuhong Yang

doi:10.1186/s12974-016-0768-3

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Regulation of effector function of CNS autoreactive CD4 T cells through inhibitory receptors and IL-7Rα

Journal article

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Regulation of effector function of CNS autoreactive CD4 T cells through inhibitory receptors and IL-7Rα

Patrick K Nuro-Gyina, Elizabeth L Rieser, Marissa C Granitto, Wei Pei, Yue Liu, Priscilla W Lee, Saba Aqel, Jian Zhang, Amy E Lovett-Racke, Michael K Racke, …

Journal of neuroinflammation, Vol.13(1), pp.302-302

12/03/2016

DOI: 10.1186/s12974-016-0768-3

PMCID: PMC5135771

PMID: 27912762

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Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

Inhibitory receptors

T cell encephalitogenicity

Experimental autoimmune encephalomyelitis (EAE)

Transcription factors

Research

Multiple sclerosis (MS)

Details

Title: Subtitle: Regulation of effector function of CNS autoreactive CD4 T cells through inhibitory receptors and IL-7Rα
Creators: Patrick K Nuro-Gyina - Postbacculaureate Research Education Program, The Ohio State University, Columbus, OH USA
Elizabeth L Rieser - Neuroscience program, College of Arts and Sciences, The Ohio State University, Columbus, OH USA
Marissa C Granitto - Neuroscience program, College of Arts and Sciences, The Ohio State University, Columbus, OH USA
Wei Pei - Department of Neurology, Wexner Medical Center, The Ohio State University, Columbus, OH USA
Yue Liu - Department of Microbial Infection and Immunity, Wexner Medical Center, The Ohio State University, Columbus, OH USA
Priscilla W Lee - Molecular Cellular and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH USA
Saba Aqel - Department of Neurology, Wexner Medical Center, The Ohio State University, Columbus, OH USA
Jian Zhang - Department of Microbial Infection and Immunity, Wexner Medical Center, The Ohio State University, Columbus, OH USA
Amy E Lovett-Racke - Department of Microbial Infection and Immunity, Wexner Medical Center, The Ohio State University, Columbus, OH USA
Michael K Racke - Department of Neurology, Wexner Medical Center, The Ohio State University, Columbus, OH USA
Yuhong Yang - Department of Neurology, Wexner Medical Center, The Ohio State University, Columbus, OH USA
Resource Type: Journal article
Publication Details: Journal of neuroinflammation, Vol.13(1), pp.302-302
DOI: 10.1186/s12974-016-0768-3
PMID: 27912762
PMCID: PMC5135771
NLM abbreviation: J Neuroinflammation
ISSN: 1742-2094
eISSN: 1742-2094
Publisher: BioMed Central; London
Grant note: PP2080 / ; 1R01NS088437-01A1; RO1 NS 067441 / ;
Language: English
Date published: 12/03/2016
Academic Unit: Pathology; Internal Medicine
Record Identifier: 9984047872902771

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