title: CTLA4-Ig immunosuppressive activity at the level of dendritic cell/T cell crosstalk.
abstract: Immunosuppressive cytotoxic T lymphocyte associated antigen-4 immunoglobulin fusion proteins (CTLA4-Ig) block the CD28:CD80/86 costimulatory pathway. On a cellular level, CTLA4-Ig is understood to dampen T cell responses. As a mechanism, CTLA4-Ig has been reported to affect dendritic cell (DC) function via inducing the immunosuppressive indoleamine 2,3 dioxygenase (IDO) pathway and promoting a DC regulatory phenotype. We here probed cellular mechanisms of CTLA4-Ig immunoregulation in an allogeneic setting using C57BL/6 splenic or bone marrow derived DCs (BMDCs) as stimulators of allogeneic Balb/c derived T cells. To address whether CTLA4-Ig immunosuppression affected DCs, we pre-exposed C57BL/6 splenic or BMDCs to CTLA4-Ig and removed unbound CTLA4-Ig before co-culture with allogeneic T cells. CTLA4-Ig disappeared rapidly (within 4 h) from the cell membrane by combined internalization and dissociation. These CTLA4-Ig pre-exposed DCs were fully capable of stimulating allogeneic T cell proliferation, suggesting that CTLA4-Ig does not impair the DC stimulatory capacity. Only the presence of CTLA4-Ig during DC/T cell co-culture resulted in the expected inhibition of proliferation. C57BL/6 splenic or BMDCs exposed to CTLA4-Ig did not display IDO activity. We conclude that CTLA4-Ig immunosuppressive activity does not depend on a DC regulatory phenotype but on its presence during DC/T cell interaction.
authors: Children's Cancer Research Institute, Division of Transplantation Immunology, Vienna, Austria.
authors: Edda
authors: E
authors: Mayer
authors: Markus
authors: M
authors: Hölzl
authors: Sarah
authors: S
authors: Ahmadi
authors: Barbara
authors: B
authors: Dillinger
authors: Nina
authors: N
authors: Pilat
authors: Dietmar
authors: D
authors: Fuchs
authors: Thomas
authors: T
authors: Wekerle
authors: Andreas
authors: A
authors: Heitger
mesh_terms: D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D006648:Histocompatibility / Q000276:immunology; D018796:Immunoconjugates / Q000494:pharmacology*; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020239:Receptor Cross-Talk; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
chemical_list: D015703:Antigens, CD; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D000069594:Abatacept