Abstracts (complete list) - Wissenschaft Online

Karin Loser, Sandra Balkow, Kerstin Klimmek, Claus Kerkhoff, Wolfgang Nacken,
Thomas A. Luger, Stefan Beissert
Autoreactive CD8+ T cell development in CD40L-mediated
autoimmunity is controlled by S100A8 and A9 proteins
CD40-CD40L signaling is involved in the development of autoimmunity and transgenic
(tg) overexpression of CD40L in basal keratinocytes spontaneously leads to systemic
autoimmunity as evidenced by autoantibodies, nephritis, proteinuria, and autoimmune
dermatitis, which can be adoptively transferred by injecting CD8+ T cells into naive
recipient mice. To identify genes involved in the development of MHC class I-restricted
autoreactivity gene expression profiling of sorted CD8+ T cells from CD40L tg mice
before and after onset of disease was performed and surprisingly, an increased
expression of S100A8 and A9 genes both members of the S100 family of Ca-binding
proteins was detected. To determine the functional relevance of S100A8/A9 expression
for the development of autoimmunity in vivo, CD40L tg mice were crossed to S100A8/
A9-/- mutants. Interestingly, CD40LxS100A8/A9-/- mice showed significantly reduced
autoimmune dermatitis and markedly decreased numbers of skin lesion infiltrating
lymphocytes. Since CD40L tg mice show renal IgG/IgM depositions and
glomerulonephritis, renal function was analyzed in CD40LxS100A8/A9-/- mice.
Importantly, CD40LxS100A8/A9-/- mice showed a complete loss of nephritis, renal
immunoglobulin depositions, and proteinuria indicating normal kidney function.
Additionally, the activation status of lymph node CD8+ T cells was determined in
CD40LxS100A8/A9-/- mice demonstrating a decreased expression of cytotoxic/
autoreactive markers like CD43 and granzyme B. CD8+ T cells isolated from
CD40LxS100A8/A9-/- mice produced significantly reduced amounts of IL-17 a cytokine
which has been suggested to mediate the inflammation associated with several
autoimmune diseases. Moreover, adoptively transferred CD8+ T cells from
CD40LXS100A8/A9-/- mice failed to elicit autoimmune dermatitis in recipient mice
indicating that the expression of S100A8/A9 proteins may be critically involved in the
pathogenesis of autoreactive MHC class I-restricted T cells in CD40L-induced systemic
autoimmunity.