Opposing T cell responses in experimental autoimmune encephalomyelitis

Naresha Saligrama; Fan Zhao; Michael J Sikora; William S Serratelli; Ricardo A Fernandes; David M Louis; Winnie Yao; Xuhuai Ji; Juliana Idoyaga; Vinit B Mahajan; Lars M Steinmetz; Yueh-Hsiu Chien; Stephen L Hauser; Jorge R Oksenberg; K Christopher Garcia; Mark M Davis

doi:10.1038/s41586-019-1467-x

Opposing T cell responses in experimental autoimmune encephalomyelitis

Nature. 2019 Aug;572(7770):481-487. doi: 10.1038/s41586-019-1467-x. Epub 2019 Aug 7.

Authors

Naresha Saligrama^{1

2}, Fan Zhao^#¹, Michael J Sikora^#³, William S Serratelli², Ricardo A Fernandes⁴, David M Louis², Winnie Yao², Xuhuai Ji⁵, Juliana Idoyaga¹, Vinit B Mahajan^{6

7}, Lars M Steinmetz^{3

8

9}, Yueh-Hsiu Chien^{1

2

10}, Stephen L Hauser¹¹, Jorge R Oksenberg¹¹, K Christopher Garcia^{4

12

13}, Mark M Davis^{14

15

16}

Affiliations

¹ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
² Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA.
³ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Human Immune Monitoring Center, Stanford University School of Medicine, Stanford, CA, USA.
⁶ Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, CA, USA.
⁷ Veterans Affairs Palo Alto Health Care, Palo Alto, CA, USA.
⁸ Stanford Genome Technology Center, Stanford University, Palo Alto, CA, USA.
⁹ European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
¹⁰ Program in Immunology, Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA.
¹¹ Department of Neurology and UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.
¹² Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
¹³ The Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
¹⁴ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
¹⁵ Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
¹⁶ The Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. [email protected].

^# Contributed equally.

Abstract

Experimental autoimmune encephalomyelitis is a model for multiple sclerosis. Here we show that induction generates successive waves of clonally expanded CD4⁺, CD8⁺ and γδ⁺ T cells in the blood and central nervous system, similar to gluten-challenge studies of patients with coeliac disease. We also find major expansions of CD8⁺ T cells in patients with multiple sclerosis. In autoimmune encephalomyelitis, we find that most expanded CD4⁺ T cells are specific for the inducing myelin peptide MOG_35-55. By contrast, surrogate peptides derived from a yeast peptide major histocompatibility complex library of some of the clonally expanded CD8⁺ T cells inhibit disease by suppressing the proliferation of MOG-specific CD4⁺ T cells. These results suggest that the induction of autoreactive CD4⁺ T cells triggers an opposing mobilization of regulatory CD8⁺ T cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Animals
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / pathology
CD8-Positive T-Lymphocytes / cytology
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / pathology
Celiac Disease
Clone Cells / cytology
Clone Cells / immunology
Encephalomyelitis, Autoimmune, Experimental / immunology*
Encephalomyelitis, Autoimmune, Experimental / pathology
Female
H-2 Antigens / immunology
Humans
Immunization
Lymphocyte Activation
Male
Mice
Mice, Inbred C57BL
Middle Aged
Myelin-Associated Glycoprotein / immunology
Receptors, Antigen, T-Cell / immunology
T-Lymphocytes / cytology
T-Lymphocytes / immunology*
T-Lymphocytes / pathology*
T-Lymphocytes, Regulatory / cytology
T-Lymphocytes, Regulatory / immunology
Young Adult

Substances

H-2 Antigens
Myelin-Associated Glycoprotein
Receptors, Antigen, T-Cell

Abstract

Publication types

MeSH terms

Substances

Grants and funding