CD28-mediated costimulation is necessary for the activation of T cell receptor-gamma delta+ T lymphocytes.
The role of costimulation in the activation of TCR-gamma delta cells in normal mice and mice transgenic (tg) for a TCR-gamma delta receptor was investigated. Activation of TCR-gamma delta cells required two signals. One signal was mediated by TCR occupancy, whereas a second signal was provided by accessory cells. The importance of the CD28/B7 interaction in the delivery of the second signal was demonstrated in multiple ways. First, addition of a soluble fusion protein homolog of CD28, CTLA4Ig, significantly inhibited the activation of G8 tg splenic TCR-gamma delta lymphocytes and intestinal epithelial TCR-gamma delta lymphocytes by Ag-bearing lymphocytes during primary stimulation. Similarly, both proliferation and IFN-gamma production were inhibited by addition of CTLA4Ig to secondary antigenic stimulation of G8 tg TCR-gamma delta cells. Second, an Ag-bearing thymoma, EL-4, was only able to stimulate expanded G8 tg TCR-gamma delta cells when the thymoma expressed B7. This stimulation was blocked by both CTLA4Ig and anti-B7 antibody. Third, antibodies to CD28 were able to mimic the costimulatory affect of APC. TCR-gamma delta cells cultured with either Ag-bearing fixed stimulator cells or submitogenic concentrations of immobilized anti-pan TCR-gamma delta mAb proliferated only in the presence of anti-CD28 mAb. Finally, G8 tg cells produced IL-2 only in the presence of APC costimulation or anti-CD28 antibodies, and the addition of exogenous rIL-2 overcame the need for costimulation. Thus, autocrine IL-2 production is one of the major consequences of TCR-gamma delta cell costimulation. Together these data demonstrate that costimulation is necessary for the activation of TCR-gamma delta cells and can occur through CD28 interaction.
Sperling
A I
AI
Ben May Institute, University of Chicago, IL 60637.
Linsley
P S
PS
Barrett
T A
TA
Bluestone
J A
JA
D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology; D000941:Antigens / Q000276:immunology; D018106:CD28 Antigens / Q000502:physiology*; D006224:Cricetinae; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis*; D013601:T-Lymphocytes / Q000276:immunology*
D000941:Antigens; D018106:CD28 Antigens; D007376:Interleukin-2; D016692:Receptors, Antigen, T-Cell, gamma-delta