Immune Autoregulatory CD8 T Cells Require IFN-γ Responsiveness to Optimally Suppress Central Nervous System Autoimmunity

Alexander W Boyden; Ashley A Brate; Laura M Stephens; Nitin J Karandikar

doi:10.4049/jimmunol.2000211

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Immune Autoregulatory CD8 T Cells Require IFN-γ Responsiveness to Optimally Suppress Central Nervous System Autoimmunity

Journal article

Peer reviewed

Immune Autoregulatory CD8 T Cells Require IFN-γ Responsiveness to Optimally Suppress Central Nervous System Autoimmunity

Alexander W Boyden, Ashley A Brate, Laura M Stephens and Nitin J Karandikar

The Journal of immunology (1950), Vol.205(2), pp.359-368

07/15/2020

DOI: 10.4049/jimmunol.2000211

PMCID: PMC7343581

PMID: 32532836

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Abstract

Investigating the complex cellular interplay controlling immunopathogenic and immunoregulatory responses is critical for understanding multiple sclerosis (MS) and for developing successful immunotherapies. Our group has demonstrated that CNS myelin-specific CD8 T cells unexpectedly harbor immune regulatory capacity in both mouse and human. In particular, PLP -specific CD8 T cells (PLP-CD8) robustly suppress the MS mouse model experimental autoimmune encephalomyelitis. We have recently shown that this depends on PLP-CD8 elaborating IFN-γ and perforin in a coordinated suppression program over time. However, the cellular target and downstream effects of CD8 T cell-derived IFN-γ remains poorly understood. In this study, we show that although wild-type (WT) PLP-CD8 were robustly suppressive in IFN-γR-deficient mice, IFN-γR-deficient PLP-CD8 exhibited suboptimal suppression in WT mice. Compared with WT counterparts, IFN-γR-deficient PLP-CD8 were defective in suppressing disease in IFN-γ-deficient recipients, a scenario in which the only IFN-γ available to WT PLP-CD8 is that which they produce themselves. Further, we found that IFN-γR-deficient PLP-CD8 exhibited altered granzyme/IFN-γ profiles, altered migration in recipients, and deficits in killing capacity in vivo. Collectively, this work suggests that IFN-γ responsiveness allows myelin-specific CD8 T cells to optimally perform autoregulatory function in vivo. These insights may help elucidate future adoptive immunotherapeutic approaches for MS patients.

Animals

Autoantigens - immunology

Autoimmunity

CD8-Positive T-Lymphocytes - immunology

Cells, Cultured

Central Nervous System - immunology

Disease Models, Animal

Encephalomyelitis, Autoimmune, Experimental - immunology

Female

Humans

Immune Tolerance

Interferon-gamma - genetics

Interferon-gamma - metabolism

Mice

Mice, Inbred C57BL

Mice, Knockout

Multiple Sclerosis - immunology

Myelin Proteolipid Protein - immunology

Myelin Sheath - immunology

Peptide Fragments - immunology

Receptors, Interferon - genetics

Receptors, Interferon - metabolism

Details

Title: Subtitle: Immune Autoregulatory CD8 T Cells Require IFN-γ Responsiveness to Optimally Suppress Central Nervous System Autoimmunity
Creators: Alexander W Boyden - University of Iowa
Ashley A Brate - University of Iowa
Laura M Stephens - University of Iowa
Nitin J Karandikar - University of Iowa
Resource Type: Journal article
Publication Details: The Journal of immunology (1950), Vol.205(2), pp.359-368
DOI: 10.4049/jimmunol.2000211
PMID: 32532836
PMCID: PMC7343581
NLM abbreviation: J Immunol
ISSN: 0022-1767
eISSN: 1550-6606
Grant note: R01 AI121567 / NIAID NIH HHS I01 BX003677 / BLRD VA R01 AI092106 / NIAID NIH HHS
Language: English
Date published: 07/15/2020
Academic Unit: Pathology
Record Identifier: 9984185171102771

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