C. Noel et al., Chronic exposure to superantigen induces regulatory CD4(+) T cells with IL-10-mediated suppressive activity, INT IMMUNOL, 13(4), 2001, pp. 431-439
The repeated injection of bacterial superantigens (SAg), such as staphyloco
ccus enterotoxin (SE) A or B, has been shown in mice to induce a state of u
nresponsiveness characterized by the lack of secretion of T(h)1 lymphokines
, such as IL-2 and IFN-gamma, following subsequent SAg challenge. We made t
he observation, in vivo as well as in vitro, that unresponsiveness to SAg c
ould be transferred from SEA- to SEE-reactive T cells land reversibly from
SEB- to SEA-specific T cells) in C57BU6 mice but not in BALB/c mice. Since
C57BL/6 mice, unlike BALB/c mice, possess TCR V(beta)3(+) and V beta 11(+)
T cells able to react with both SEA and SEE, we hypothesized that SAg-unres
ponsive V(beta)3(+) and V(beta)11(+) T cells could mediate linked suppressi
on of other SAg-reactive T cells. To analyze further this possibility, sple
en cells from BALB/c mice made unresponsive to SEE were tested for their ca
pacity to suppress the response of normal BALB/c cells to SEE. The producti
on of both IFN-gamma and IL-2 following SEE stimulation was greatly impaire
d in co-cultures containing CD4(+) T cells, but not CD8(+) T cells, isolate
d from unresponsive animals. In vivo, the production of both IFN-1 and IL-2
responses to SEB was dramatically reduced in animals adoptively transferre
d with unresponsive spleen cells. This suppression was abrogated in recipie
nts injected with neutralizing anti-IL-10 antibodies. Moreover, in animals
made unresponsive to SEE, SAg-reactive CD4(+) T cells were found to express
high levels of CTLA-4, a molecule recently described to play an essential
role in the suppressive function of regulatory T cells. Taken together thes
e results demonstrate that the repetitive injection of SAg induces the diff
erentiation of regulatory CD4+ T cells capable of suppressing SAg-reactive
naive T cells.