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Infection and Immunity, July 2008, p. 3045-3053, Vol. 76, No. 7
0019-9567/08/$08.00+0     doi:10.1128/IAI.00193-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Deficiency of Indoleamine 2,3-Dioxygenase Enhances Commensal-Induced Antibody Responses and Protects against Citrobacter rodentium-Induced Colitis{triangledown}

Lynne Harrington,1 Chittur V. Srikanth,1 Reuben Antony,1 Sue J. Rhee,1,{dagger} Andrew L. Mellor,3 Hai Ning Shi,1,2 and Bobby J. Cherayil1,2*

Mucosal Immunology Laboratory, Pediatric Gastroenterology Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02129,1 Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115,2 Immunotherapy Center, Medical College of Georgia, Augusta, Georgia 309123

Received 12 February 2008/ Returned for modification 21 March 2008/ Accepted 13 April 2008

Indoleamine 2,3-dioxygenase (IDO) is a negative regulator of lymphocyte responses that is expressed predominantly in macrophages and dendritic cells. We detected it at high levels in the small intestine and mesenteric lymph node of young adult mice, suggesting a role in intestinal immunity. Consistent with this idea, we found that IDO-deficient mice had elevated baseline levels of immunoglobulin A (IgA) and IgG in the serum and increased IgA in intestinal secretions. These abnormalities were corrected by a course of broad-spectrum oral antibiotics started at weaning, indicating that they were dependent on the intestinal microbiota. Kynurenine and picolinic acid, two IDO-generated metabolites of tryptophan, were able to inhibit lipopolysaccharide-induced antibody production by splenocytes in vitro, and kynurenine also induced B-cell apoptosis, findings that provide an explanation for the elevated Ig levels in animals lacking IDO. The intestinal secretions of IDO-deficient mice had elevated levels of IgA antibodies that cross-reacted with the gram-negative enteric bacterial pathogen Citrobacter rodentium. In keeping with the functional importance of this natural secretory IgA, the mutant animals were more resistant to intestinal colonization by Citrobacter, developed lower levels of serum Citrobacter-specific IgM and IgG antibodies following oral infection, and had significantly attenuated Citrobacter-induced colitis. Our observations point to an important role for IDO in the regulation of immunity to the gut commensal microbiota that has a significant impact on the response to intestinal pathogens.

* Corresponding author. Mailing address: Pediatric Gastroenterology Unit, Building 114, 16th Street, Charlestown, MA 02129. Phone: (617) 726-4170. Fax: (617) 726-4172. E-mail: cherayil{at}helix.mgh.harvard.edu

{triangledown} Published ahead of print on 21 April 2008.

Editor: S. R. Blanke

{dagger} Present address: Pediatric Intestinal Rehabilitation and Transplant Program, University of California, San Francisco, CA 94143.

Infection and Immunity, July 2008, p. 3045-3053, Vol. 76, No. 7
0019-9567/08/$08.00+0     doi:10.1128/IAI.00193-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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