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Infection and Immunity, November 2005, p. 7226-7235, Vol. 73, No. 11
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.11.7226-7235.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

CD4⁺-T-Cell Responses Generated during Murine Salmonella enterica Serovar Typhimurium Infection Are Directed towards Multiple Epitopes within the Natural Antigen FliC

Molly A. Bergman,^1, Lisa A. Cummings,² Robert C. Alaniz,² Laura Mayeda,² Ivana Fellnerova,² and Brad T. Cookson^1,2*

Departments of Microbiology,¹ Laboratory Medicine, University of Washington, Seattle, Washington²

Received 29 March 2005/ Returned for modification 5 July 2005/ Accepted 1 August 2005

The flagellar filament protein FliC is a natural antigen recognized by memory CD4⁺ T cells recovered from Salmonella enterica serovar Typhimurium-infected humans and mice. To further investigate T-cell responses to FliC, we derived FliC-specific CD4⁺-T-cell clones from mice of two different haplotypes following oral S. enterica serovar Typhimurium infection. Using C-terminal truncations of MalE-FliC recombinant fusion proteins, we mapped antigenic activity to four different regions of FliC; three of the four epitope-containing regions were present in both FliC and the alternate flagellin subunit FljB. We determined that two novel FliC epitopes were also present in flagellins from several gram-negative enteric bacterial species: E^k-restricted FliC 80-94 (amino acids 80 to 94) and A^b-restricted FliC 455-469. Further mapping confirmed the presence of two previously identified FliC epitopes: A^k-restricted FliC 339-350 and A^b-restricted FliC 428-442. Therefore, like the recognition site of the innate immune receptor Toll-like receptor 5, three of four FliC epitopes recognized by CD4⁺ T cells colocalize in the D0/D1 domains of FliC. Salmonella-infected macrophages and dendritic cells stimulated epitope-specific CD4⁺-T-cell proliferation; infected dendritic cells also activated T cells to produce gamma interferon. These data demonstrate that Salmonella infection generates murine CD4⁺-T-cell responses to multiple epitopes in the natural antigen FliC and that recognition of infected phagocytes by FliC-specific CD4⁺ T cells triggers effector functions known to be essential for protective immunity. Together, these data suggest that FliC-specific CD4⁺ T cells may contribute to cell-mediated host defenses against Salmonella.

Editor: V. J. DiRita

Present address: Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02112.

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