title: γδ T Cell-Dependent Regulatory T Cells Prevent the Development of Autoimmune Keratitis.
abstract: To prevent potentially damaging inflammatory responses, the eye actively promotes local immune tolerance via a variety of mechanisms. Owing to trauma, infection, or other ongoing autoimmunity, these mechanisms sometimes fail, and an autoimmune disorder may develop in the eye. In mice of the C57BL/10 (B10) background, autoimmune keratitis often develops spontaneously, particularly in the females. Its incidence is greatly elevated in the absence of γδ T cells, such that ∼80% of female B10.TCRδ(-/-) mice develop keratitis by 18 wk of age. In this article, we show that CD8(+) αβ T cells are the drivers of this disease, because adoptive transfer of CD8(+), but not CD4(+), T cells to keratitis-resistant B10.TCRβ/δ(-/-) hosts induced a high incidence of keratitis. This finding was unexpected because in other autoimmune diseases, more often CD4(+) αβ T cells, or both CD4(+) and CD8(+) αβ T cells, mediate the disease. Compared with wild-type B10 mice, B10.TCRδ(-/-) mice also show increased percentages of peripheral memory phenotype CD8(+) αβ T cells, along with an elevated frequency of CD8(+) αβ T cells biased to produce inflammatory cytokines. In addition, B10.TCRδ-/- mice have fewer peripheral CD4(+) CD25(+) Foxp3(+) αβ regulatory T cells (Tregs), which express lower levels of receptors needed for Treg development and function. Together, these observations suggest that in B10 background mice, γδ T cells are required to generate adequate numbers of CD4(+) CD25(+) Foxp3(+) Tregs, and that in B10.TCRδ(-/-) mice a Treg deficiency allows dysregulated effector or memory CD8(+) αβ T cells to infiltrate the cornea and provoke an autoimmune attack.
authors.affiliation: Department of Biomedical Research, National Jewish Health, Denver, CO 80206; Department of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045; Joint Laboratory for Stem Cell Engineering and Technology Transfer, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City 430030, People's Republic of China;
authors.forename: Yafei
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Biomedical Research, National Jewish Health, Denver, CO 80206; Department of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045; Department of Breast and Thyroid Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City 430030, People's Republic of China; and.
authors.forename: Zhifang
authors.identifier: http://orcid.org/0000-0003-2400-7488
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Biomedical Research, National Jewish Health, Denver, CO 80206;
authors.forename: Chunjian
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Biomedical Research, National Jewish Health, Denver, CO 80206;
authors.forename: Jessica
authors.initials: J
authors.lastname: McGowan
authors.affiliation: Department of Biomedical Research, National Jewish Health, Denver, CO 80206;
authors.forename: Tamara
authors.initials: T
authors.lastname: Casper
authors.affiliation: Doheny Eye Institute, Department of Ophthalmology, University of Southern California, Los Angeles, CA 90033.
authors.forename: Deming
authors.identifier: http://orcid.org/0000-0003-4851-0416
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Biomedical Research, National Jewish Health, Denver, CO 80206; Department of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045;
authors.forename: Willi K
authors.initials: WK
authors.lastname: Born
authors.affiliation: Department of Biomedical Research, National Jewish Health, Denver, CO 80206; Department of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045; obrienr@njhealth.org.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D003315:Cornea / Q000276:immunology*; D018450:Disease Progression; D005260:Female; D051858:Forkhead Transcription Factors; D007156:Immunologic Memory; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007634:Keratitis / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta