Bordetella pertussis uses the induction of pathogen-specific regulatory T cells to subvert the protective T helper 1 (TH1) response.
Although the concept of T-cell-mediated suppression went out of favour for a while during the 1980s, by the mid-1990s regulatory T cells were back in vogue. Much has been learned in recent years, but the nature of the antigens recognized by regulatory T cells and the factors controlling their induction in vivo remain unknown. Reporting in the Journal of Experimental Medicine, Kingston Mills' group now report for the first time the induction of pathogen-specific regulatory T cells and show that this is a mechanism used by Bordetella pertussis to subvert the protective T helper 1 (TH1) response.
B. pertussis is a pathogen of the respiratory tract. Recovery from infection is dependent on the development of B. pertussis-specific TH1 cells, although the TH1 response is suppressed during the acute phase of infection. Previous work by Mills et al. has shown that the B. pertussis virulence factor filamentous haemagglutinin (FHA) can inhibit lipopolysaccharide (LPS)-stimulated interleukin-12 (IL-12) production by macrophages. In the present study, the role of FHA in suppression of TH1 responses by induction of regulatory T cells was examined.
The authors first looked at the effect of FHA on cytokine production by immature bone-marrow-derived dendritic cells (DCs). FHA stimulated IL-10 production by DCs and suppressed LPS- and interferon- (IFN-)-induced production of IL-12. Because IL-10 seems to be required for the induction of T regulatory 1 (Tr1) cells, the authors next looked for evidence of Tr1 induction during the acute phase of responses to B. pertussis, when TH1 responses are suppressed. Tr1-like lines and clones were derived from the lungs of mice acutely infected with B. pertussis by culturing lung T cells with antigen-presenting cells (APCs) and FHA (which stimulates IL-10 production by the APCs). The Tr1 clones secreted high levels of IL-10 and IL-5 and moderate levels of transforming growth factor-, but little or no IFN-, IL-2 or IL-4.
So can these Tr1 clones suppress TH1 responses to B. pertussis? The effect of Tr1 cells was examined in vivo using adoptive transfer experiments in sublethally irradiated mice. Adoptive transfer of B. pertussis-specific TH1 cells into infected mice induced IFN- production and bacterial clearance by 3 weeks. By contrast, co-transfer of Tr1 cells suppressed IFN- production and delayed bacterial clearance. In vitro experiments suggested that the mechanism of suppression was via soluble IL-10, which induces the differentiation of Tr1 cells.
The results show that FHA interacts with DCs to promote the production of IL-10 and induce the development of regulatory T cells. Analogous to IL-12 for TH1 cells, IL-10 seems to be an essential differentiation, but not growth, factor for Tr1 cells. The induction of pathogen-specific Tr1 cells is a novel strategy for the evasion of protective immune responses.
Elaine Bell
References
ORIGINAL RESEARCH PAPER McGuirk, P., McCann, C. & Mills, K. H. G. Pathogen-specific T regulatory 1 cells induced in the respiratory tract by a bacterial molecule that stimulates interleukin 1 production by dendritic cells: a novel strategy for evasion of protective helper type 1 responses by Bordetella pertussis. J. Exp. Med.195, 221–231 (2002). | PubMed |
FURTHER READING Read, S. & Powrie, F. CD4(+) regulatory T cells. Curr. Opin. Immunol.13, 644–649. | PubMed |
(
