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Vaccine-Induced Antibody Isotypes Are Skewed by Impaired CD4 T Cell and Invariant NKT Cell Effector Responses in MyD88-Deficient Mice¹

Onyinye I. Iweala^2,*, Donald W. Smith^2,*, Kabir S. Matharu^*, Isabel Sada-Ovalle, Deanna D. Nguyen, Rosemarie H. DeKruyff, Dale T. Umetsu, Samuel M. Behar and Cathryn R. Nagler^3,*

^* Center for Immunology and Inflammatory Disease, Division of Rheumatology, Allergy and Immunology and Gastrointestinal Unit, Massachusetts General Hospital, Charlestown, MA 02129; and Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital and Children’s Hospital and Harvard Medical School, Boston, MA 02115

The requirement for TLR signaling in the initiation of an Ag-specific Ab response is controversial. In this report we show that a novel OVA-expressing recombinant Salmonella vaccine (Salmonella-OVA) elicits a Th1-biased cell-mediated and serum Ab response upon oral or i.p. immunization of C57BL/6 mice. In MyD88^–/– mice, Th1-dependent Ab responses are greatly reduced while Th2-dependent Ab isotypes are elevated in response to oral and i.p., but not s.c. footpad, immunization. When the T effector response to oral vaccination is examined we find that activated, adoptively transferred Ag-specific CD4⁺ T cells accumulate in the draining lymph nodes, but fail to produce IFN-, in MyD88^–/– mice. Moreover, CD1d tetramer staining shows that invariant NKT cells are activated in response to oral Salmonella-OVA vaccination in wild-type, but not MyD88^–/–, mice. Treatment with neutralizing Ab to CD1d reduces the OVA-specific Ab response only in MyD88-sufficient wild-type mice, suggesting that both Ag-specific CD4 T cell and invariant NKT cell effector responses to Salmonella-OVA vaccination are MyD88 dependent. Taken together, our data indicate that the type of adaptive immune response generated to this live attenuated vaccine is regulated by both the presence of MyD88-mediated signals and vaccination route, which may have important implications for future vaccine design.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant DK 55678, the Massachusetts General Hospital Center for the Study of Inflammatory Bowel Disease (Grant DK 43551), and Predoctoral Training Fellowships T32 A107529 (to D.W.S.) and F31 AI054229 (to O.I.I.).

² O.I.I. and D.W.S. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Cathryn R. Nagler, BSD/Department of Pathology, Committee on Immunology, The University of Chicago, 5841 South Maryland Avenue MC 3083, Chicago, IL 60637. E-mail address: cnagler{at}bsd.uchicago.edu

⁴ Abbreviations used in this paper: iNKT, invariant NKT; DC, dendritic cell; MLN, mesenteric lymph node; WT, wild type.