Abstracts (complete list) - Wissenschaft Online

Eric Keil, Nana Ueffing, Linda Clayton, Ellis Reinherz, Klaus Schulze-Osthoff, Ingo
Schmitz
Expression profiling identifies Gadd45β as a novel mediator of
negative selection
Apoptosis is essential for the development of multicellular organisms and its
deregulation may lead to various diseases. In the immune system, reduced apoptosis
results in the accumulation of autoreactive T cells leading to impaired tolerance and
autoimmunity. Autoimmune diseases like type I diabetes or multiple sclerosis arise from
defects in peripheral tolerance, while the autoimmune polyglandular syndrome type 1
(APS-1 or APECED) is due to impaired central tolerance, i.e. negative selection. To get
further insights into the process of negative selection we have analyzed gene induction
during peptide-induced negative selection in vivo by oligonucleotide arrays. The most
strongly induced gene was Gadd45β, which is implicated in differentiation and
apoptosis. Upregulation of Gadd45β was verified on the mRNA and protein level by
quantitative PCR and Western blotting, respectively. Importantly, Gadd45β-expression
in vivo was stimulated by peptides inducing negative selection but not by those inducing
positive selection. In situ hybridization supported a role for Gadd45β in negative
selection as its mRNA was specifically expressed in the medulla. Finally, overexpression
of Gadd45β induced apoptosis in CD4+CD8+ double positive T cells. Thus, Gadd45β
may induce a yet unrecognized pathway for clonal deletion in the thymus next to the
established once induced by Bim, Nur77 and FasL/CD95L.