T helper-independent activation of human CD8+ cells: the role of CD28 costimulation.
The concept that activation of MHC class I-restricted CD8+ cells entirely depends on help from MHC class II-restricted CD4+ T cells has recently been supplemented with an alternative model in which CD8+ cells can directly be activated by MHC class I-expressing professional antigen-presenting cells (APC), which are able to deliver an accessory signal. The authors analysed the role of CD28-mediated costimulation for T helper cell-independent activation of purified human CD8+ T cells in two different in vitro models. Freshly isolated CD8+ cells could be activated (proliferation, IL-2 production and cytotoxic activity) by anti-CD3-presenting Fc gamma R+ mouse cells transfected with the human CD28 ligand, CD80, as the only accessory signal. On the other hand, activation of CD8+ cells by allogeneic MHC class I on EBV-transformed B cells, which express two different CD28 ligands, CD80 and CD86, also proceeded very efficiently (proliferation, cytotoxic activity and CD25 expression), but was either not, or only partially, blocked by anti-CD80 and anti-CD86 MoAb or CTLA-4Ig. This indicates that other costimulatory signals are also effective, and that CD28 triggering is not absolutely required for initial T-cell activation. CsA and CD80/CD86-blocking agents were synergistic in completely inhibiting activation of CD8+ cells in the MLR with allogeneic B-cell lines. This combination also induced non-responsiveness of CD8+ cells upon restimulation in the absence of blocking agents. Therefore, although professional APC can apparently provide multiple costimulatory signals for direct activation of CD8+ T cells, the signal derived from CD80/CD86 is unique in providing CsA-resistance.
Van Gool
S W
SW
Department of Pathophysiology, Catholic University of Leuven, Belgium.
Zhang
Y
Y
Kasran
A
A
de Boer
M
M
Ceuppens
J L
JL
D000069594:Abatacept; D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000494:pharmacology; D018122:B7-1 Antigen / Q000494:pharmacology; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D060908:CTLA-4 Antigen; D002469:Cell Separation; D002478:Cells, Cultured; D017635:Clonal Anergy; D016572:Cyclosporine / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004357:Drug Synergism; D000939:Epitopes / Q000494:pharmacology; D005260:Female; D006801:Humans; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007519:Isoantigens / Q000494:pharmacology; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008875:Middle Aged; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D000939:Epitopes; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D007519:Isoantigens; D008024:Ligands; D015375:Receptors, Interleukin-2; D000069594:Abatacept; D016572:Cyclosporine