Pathogen-specific Tr1 cells induced by bacteria & 1/21/02 JEM
BiGol...@aol.com
providing evidence that a bacterial molecule induces formation of
pathogen-specific T regulatory cells that produce high levels of IL-10,
but not IL-4 or IFN-gamma.
McGuirk et al. state:
"Here we provide the first demonstration of pathogen-specific
T regulatory type 1 (Tr1) cells at the clonal level and demonstrate that
these cells are induced at a mucosal surface during an infection where
local Th1 responses are suppressed. Tr1 clones specific for filamentous
hemagglutinin (FHA) and pertactin were generated from the lungs of mice
during acute infection with B. pertussis."
"Taken together with our demonstration of inhibition of IL-12 and
inflammatory chemokines and stimulation of IL-10-producing DCs that
directs the induction of Tr1 cells, the net effect of FHA is to inhibit
the induction, activation and recruitment of Th1 cells. This represents
a novel immune subversion strategy employed by a respiratory tract
pathogen to prolong its survival in the host."
As concerns HIV, high-dose antigen, and tolerance, Steinman &
Nussenzweig state: "However, in the case of HIV, the amount of antigen
and the targeting of virus to receptors on immature DCs should intensify
immune evasion through the induction of tolerance" (Proc Natl Acad Sci
USA 2002, 99:351-358).
As concerns the history of "immunological paralysis" by pathogens,
Felton et al. (J Immunol 1955; 74:17-26) state:
"Immunological paralysis has been defined as that condition produced in
the host by an antigen given in such amount that a subsequent immunizing
does fails to stimulate active immunity."
"The antagonistic effect of a large does of antigen was recognized at
least as long ago as Metchnikoff's studies in 1883 of the inhibition of
phagocytosis by too large a dose of yeast spores; and it was shown to
persist for weeks or even months in experimental animals in the studies
by Courmont on "substances soluble favorisants" produced by
staphylococci and tubercle bacilli. With pneumococci, Rosenow in 1897
reported in vitro inhibition of phagocytosis by "virulins" which
presumably were (or contained) the polysaccharides. Thus from these and
many other investigators the concept of a prozone of "immunological
paralysis" is well known. The present investigation demonstrates that
mice once inoculated with such a "paralyzing" dose of pneumococcus
polysaccharide can no longer be immunized with any dose of isolated
homologous polysaccharide at any time during the life span studies."
---------------------------------
The Journal of Experimental Medicine, Volume 195, Number 2, January 21,
2002 221-231
Pathogen-specific T Regulatory 1 Cells Induced in the Respiratory Tract
by a Bacterial Molecule that Stimulates Interleukin 10 Production by
Dendritic Cells
A Novel Strategy for Evasion of Protective T Helper Type 1 Responses by
Bordetella pertussis
Peter McGuirk, Chantelle McCann and Kingston H.G. Mills
Immune Regulation Research Group, Department of Biochemistry, Trinity
College, Dublin 2, Ireland
Address correspondence to Prof. Kingston Mills, Department of
Biochemistry, Trinity College, Dublin 2, Ireland. Phone: 353-1-6083573;
Fax: 353-1-6772400; E-mail: kingsto...@tcd.ie
Abstract: Antigen-specific T helper type 1 (Th1) cells mediate
protective immunity against a range of infectious diseases, including
that caused by Bordetella pertussis. Distinct T cell subtypes that
secrete interleukin (IL)-10 or tumor growth factor (TGF)-beta are
considered to play a role in the maintenance of self-tolerance.
However, the antigens recognized by these regulatory T cells in vivo
have not been defined. Here we provide the first demonstration of
pathogen-specific T regulatory type 1 (Tr1) cells at the clonal level
and demonstrate that these cells are induced at a mucosal surface during
an infection where local Th1 responses are suppressed. Tr1 clones
specific for filamentous hemagglutinin (FHA) and pertactin were
generated from the lungs of mice during acute infection with B.
pertussis. The Tr1 clones expressed T1/ST2 and CC chemokine receptor 5,
secreted high levels of IL-10, but not IL-4 or interferon (IFN)-gamma,
and suppressed Th1 responses against B. pertussis or an unrelated
pathogen. Furthermore, FHA inhibited IL-12 and stimulated IL-10
production by dendritic cells (DCs), and these DCs directed naive T
cells into the regulatory subtype. The induction of Tr1 cells after
interaction of a pathogen-derived molecule with cells of the innate
immune system represents a novel strategy exploited by an infectious
pathogen to subvert protective immune responses in vivo.