THE NATURE OF THE SIGNALS REGULATING CD8 T-CELL PROLIFERATIVE RESPONSES TO CD8-ALPHA(-ALPHA(-) DENDRITIC CELLS() OR CD8)

The CD8 alpha(-) -expressing dendritic cells (DC) of mouse spleen have been shown to be poor inducers of interleukin (IL)-2 production by CD 8 T cells when compared to the CD8(-) DC. As a consequence, CD8 T cell s give a more prolonged proliferative response to CD8(-) DC than to CD 8(+) DC. The possible mechanisms underlying these functional differenc es in DC sub-type have been investigated. Inadequate co-stimulation di d not underlie the poor T cell response to allogeneic CD8(+) DC. Equiv alent levels of B7-1 (CD80) and B7-2 (CD86) were found on the two DC s ubtypes and co-stimulator assays did not reveal any functional differe nces between them. Although CD8(+) DC were found to die more rapidly i n culture than CD8(-) DC, this did not explain their reduced stimulato ry ability. Neither prolonging DC survival in culture nor renewing the stimulator cells by repeated addition of freshly isolated DC had any significant effect on the T cell responses. Furthermore, later additio n to the cultures of DC of the opposite type to the initiating DC did not reverse or eliminate the differential response to the initiating D C. The role of DC-derived soluble factors was examined by addition to the cultures of supernatants derived from freshly isolated or stimulat ed DC of the opposite type. This neither enhanced the poor stimulatory capacity of CD8(+) DC nor inhibited the stimulation by CD8(-) DC. Fur thermore, addition of a series of cytokines that might have been produ ced by the DC did not eliminate the differences in T cell proliferatio n. Only the addition to the cultures of the growth factors IL-2 and IL -4 overcame the stimulatory difference between the two DC populations, confirming that the difference in T cell proliferative responses was a consequence of differences in induced cytokine production. The diffe rence in the response of CD8 T cells to CD8(+) and CD8(-) DC is theref ore determined by direct DC-T cell contact during the earliest stages of the culture and involves an undetermined and possibly new signaling system.