Kruppel-like factor 2+ CD4 T cells avert microbiota-induced intestinal inflammation
Tzu-Yu Shao,
Tony T. Jiang,
Joseph Stevens,
Abigail E. Russi,
Ty D. Troutman,
Anas Bernieh,
Giang Pham,
John J. Erickson,
Emily M. Eshleman,
Theresa Alenghat,
Stephen C. Jameson,
Kristin A. Hogquist,
Casey T. Weaver,
David B. Haslam,
Hitesh Deshmukh,
Sing Sing Way
Affiliations
Tzu-Yu Shao
Division of Infectious Diseases, Center for Inflammation and Tolerance, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
Tony T. Jiang
Division of Infectious Diseases, Center for Inflammation and Tolerance, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
Joseph Stevens
Division of Neonatology and Pulmonary Biology, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
Abigail E. Russi
Division of Gastroenterology, Hepatology and Advanced Nutrition, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
Ty D. Troutman
Division of Allergy and Immunology, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
Anas Bernieh
Division of Pathology, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
Giang Pham
Division of Infectious Diseases, Center for Inflammation and Tolerance, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
John J. Erickson
Division of Neonatology and Pulmonary Biology, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
Emily M. Eshleman
Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
Theresa Alenghat
Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
Stephen C. Jameson
Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
Kristin A. Hogquist
Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
Casey T. Weaver
Program in Immunology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35233, USA
David B. Haslam
Division of Infectious Diseases, Center for Inflammation and Tolerance, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
Hitesh Deshmukh
Division of Neonatology and Pulmonary Biology, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
Sing Sing Way
Division of Infectious Diseases, Center for Inflammation and Tolerance, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA; Corresponding author
Summary: Intestinal colonization by antigenically foreign microbes necessitates expanded peripheral immune tolerance. Here we show commensal microbiota prime expansion of CD4 T cells unified by the Kruppel-like factor 2 (KLF2) transcriptional regulator and an essential role for KLF2+ CD4 cells in averting microbiota-driven intestinal inflammation. CD4 cells with commensal specificity in secondary lymphoid organs and intestinal tissues are enriched for KLF2 expression, and distinct from FOXP3+ regulatory T cells or other differentiation lineages. Mice with conditional KLF2 deficiency in T cells develop spontaneous rectal prolapse and intestinal inflammation, phenotypes overturned by eliminating microbiota or reconstituting with donor KLF2+ cells. Activated KLF2+ cells selectively produce IL-10, and eliminating IL-10 overrides their suppressive function in vitro and protection against intestinal inflammation in vivo. Together with reduced KLF2+ CD4 cell accumulation in Crohn’s disease, a necessity for the KLF2+ subpopulation of T regulatory type 1 (Tr1) cells in sustaining commensal tolerance is demonstrated.
