Abstracts (complete list) - Wissenschaft Online

Holger Hoff, Zulema Cabail, Karin Knieke, Marion Rudolph, Heike Hirseland, Barbara
Bröker, Monika Brunner-Weinzierl
CD152 (CTLA-4) controls CD28-independently cell cycle
progression and resistance against apoptosis of human T
lymphocytes
The activation of T-lymphocytes is tightly controlled by positive and negative costimulatory
receptors. Primary costimulatory molecules are CD28 and CD152 (CTLA-4)
of the Ig-superfamily. Both are stimulated by the same ligands B7-1 (CD80) and B7-2
(CD86) on antigen-presenting cells. While CD28 is mediating positive co-stimulatory
signals the crosslinking of CD152 leads to cell-cycle arrest and reduced production of
cytokines, but CD28 as well as CD152-mediated signals induce resistance against
activation-induced cell death (AICD). A subpopulation of human T-helper cells (CD4+)
and cytotoxic T cells (CD8+) that has lost the expression of CD28 (CD28null T cells)
show reduced proliferation and longevity. In this study we could show that despite the
loss of CD28 expression these cells are able to express CD152 at their cell surface
shortly after beginning of their stimulation. Their surface CD152 is functional as the
serological blockade of CD152 leads to enhanced proliferation of CD4 and CD8 CD28null
T lymphocytes. In addition we were able to show that blockade of CD152 signal
transduction using CD152 Fab-fragments during stimulation leads to enhanced induction
of apoptosis. The anti-apoptotic effect of CD152 was confirmed by cross-linking of
CD152 which leads to reduced activation of caspases. The CD152-mediated resistance
against apoptosis is mediated by enhanced activation of the anti-apoptotic kinase Akt.
Thus, surface CD152 expression and CD152-mediated signalling is independent of CD28signalling.
These data also demonstrate that CD152 initiates CD28-independent
induction of anti-apoptotic signalling pathways.