T-HELPER-INDEPENDENT ACTIVATION OF HUMAN CD8(- THE ROLE OF CD28 COSTIMULATION() CELLS )

The concept that activation of MHC class I-restricted CD8(+) cells ent irely depends on help from MHC class II-restricted CD4(+) T cells has recently been supplemented with an alternative model in which CD8(+) c ells 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 ce lls in two different in vitro models. Freshly isolated CD8(+) cells co uld be activated (proliferation, IL-2 production and cytotoxic activit y) by anti-CD3-presenting Fc gamma R(+) mouse cells transfected with t he human CD28 ligand, CD80, as the only accessory signal. On the other hand, activation of CD8(+) cells by allogeneic MHC class I on EBV-tra nsformed B cells, which express two different CD28 ligands, CD80 and C D86, also proceeded very efficiently (proliferation, cytotoxic activit y and CD25 expression), but was either not, or only partially, blocked by anti-CD80 and anti-CD86 MoAb or CTLA-4Ig. This indicates that othe r costimulatory signals are also effective, and that CD28 triggering i s not absolutely required for initial T-cell activation. CsA and CD80/ CD86-blocking agents were synergistic in completely inhibiting activat ion of CD8(+) cells in the MLR with allogeneic B-cell lines. This comb ination also induced non-responsiveness of CD8(+) cells upon restimula tion in the absence of blocking agents. Therefore, although profession al APC can apparently provide multiple costimulatory signals for direc t activation of CD8(+) T cells, the signal derived from CD80/CD86 is u nique in providing CsA-resistance.