Abstracts (complete list) - Wissenschaft Online

Alla Skapenko, Joachim R. Kalden, Peter E. Lipsky, Hendrik Schulze-Koops
In vivo function of IL-4-induced Tregs
We have previously shown that injection of human peripheral blood mononuclear cells
(PBMC) into the peritoneal cavity of NOD/SCID mice results in the development of a
Th1-mediated immune response of human cells against murine tissue accompanied by
an increase in the frequency of CD25+CD4+ T cells. Here, we used this model to
analyze the role of interleukin (IL)-4 in the generation of human CD25+ regulatory T
cells in an in vivo situation. NOD/SCID mice were injected intraperitoneally with human
PBMC and treated with human IL-4 or a neutralizing antibody to human IL-4. IL-4treatment
down-modulated systemic inflammation as assessed by a decrease of serum
levels of the human inflammatory cytokines, TNF and IFN-gamma whereas
neutralization of endogenous IL-4 resulted in an exaggeration of inflammation. Analysis
of the frequencies of CD25+CD4+ T cells within the human cells recovered from the
peritoneal cavity of the mice revealed that treatment with IL-4 augmented and IL-4
neutralization diminished the increase of CD25+CD4+ T cells associated with the
immune response. Examination of the immunosuppressive ability of recovered human T
cells in vitro revealed an inhibititory capacity of CD25+, but not of CD25- T cells, for the
proliferative response of autologous PBMC. Importantly, when injected into animals with
an ongoing Th1-mediated immune reaction driven by syngeneic human PBMC, purified
CD25+ T cells were able to reduce serum levels of human IFN-gamma and TNF,
whereas injection of CD25- T cells resulted in increased levels of both cytokines. Thus,
CD25+ Tregs that developed in vivo in the presence of IL-4 were functionally competent
Tregs. This conclusion is supported by the fact that the frequency of CD25+CD4+ T
cells recovered from the peritoneal cavity at the peak of the xenogeneic reaction in mice
injected with human PBMC inversely correlated with serum concentrations of human
IFN-gamma and TNF. Together, the data indicate that CD25+CD4+ T cells which
accumulate during the Th1-mediated immune response of human cells in NOD/SCID
mice possess an immunosuppressive phenotype in vivo. Moreover, the data further
imply that IL-4 controls the generation of competent CD25+ Tregs during an immune
response in vivo.