Mechanismus der CD28-vermittelten Induktion der T-Zellproliferation

• Antragsteller: Professor Dr. Thomas Hünig
• Fachliche Zuordnung: Immunologie
• Förderung: Förderung von 2003 bis 2006
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 5398154

Naive T cells require stimulation through both the antigen-specific T cell receptor (TCR) and the co-stimulatory molecule CD28 to proliferate and respond to an immune challenge. Mitogenic anti-rat CD28 antibody, which induces T cell proliferation independent of TCR engagement, provides an exception to this two-signal requirement, and hence a unique opportunity to define CD28-mediated signalling events leading to proliferation. We have shown biochemically in primary cells that proximal TCR signalling is not required for mitogenic anti-CD28 antibody stimulation. Surprisingly however, a comparison of TCR-deficient and -reconstituted cell lines showed that surface expression of the TCR was required. We will: * use T cell lines deficient in proximal TCR signalling molecules to define what TCR signalling components are required, and * generate and characterize novel mitogenic anti-mouse CD28 antibodies in order to study mitogenic CD28 signalling in mice genetically deficient in various signalling molecules. Recent results from our group have identified the epitope selectively recognized by mitogenic anti-CD28 antibody. The topology of the epitope restricts bivalent antibody binding to bridging of neighbouring CD28 homodimers, and suggests that a lattice structure of CD28/CD80 complexes analogous to those formed by CTLA-4/CD80 complexes is important for mitogenic activity. Accordingly, we will examine: * the effect of mitogenic antibody on the interaction of CD28 with its natural ligand CD80, * the hypothesised multimerisation of CD28 by mitogenic antibody to form a CTLA-4 lattice-like structure, and * the hypothesised recognition of a subset of CD28 molecules preclustered in membrane microdomains by mitogenic antibody. An understanding of the basis of CD28 signalling may define how CD28 contributes to physiological co-stimulation.

• DFG-Verfahren: Sachbeihilfen