Deletion of flagellin´s hypervariable region abrogates antibody-mediated neutralization and systemic activation of TLR5-dependent immunity.

NEMPONT C; CAYET D; RUMBO M; BOMPARD C; VILLERET V; SIRARD JC

JOURNAL OF IMMUNOLOGY

AMER ASSOC IMMUNOLOGISTS

Año: 2008 vol. 181 p. 2036 - 2043

0022-1767

Toll-like receptors (TLR) trigger immunity upon detection of microbe-associated molecular patterns (MAMP). Flagellin is a unique MAMP since it harbors (1) an antigenic hypervariable domain and (2) a domain involved in TLR5-dependent systemic and mucosal pro-inflammatory and adjuvant activities. Using wild type and recombinant flagellins, we showed in vitro and in vivo that TLR5 signaling can be neutralized by flagellin-specific antibodies. Therefore, MAMP-specific antibodies can block in vivo TLR-mediated response, indicating that such neutralization is a novel mechanism of negative regulation of innate immunity. Deletion of hypervariable domain abrogated the intrinsic ability of flagellin to trigger neutralizing antibodies and systemic responses. In contrast, the mucosal TLR5 stimulatory functions of flagellin were not altered by deletion, suggesting distinct mechanisms for TLR5 activation in systemic compared to mucosal compartments. In conclusion, specific MAMP molecular determinants control the development of neutralizing antibodies and the compartmentalization of innate responses.