The nature of the signals regulating CD8 T cell proliferative responses to CD8 alpha super(+) or CD8 alpha super(-) dendritic cells

The CD8 alpha super(-)-expressing dendritic cells (DC) of mouse spleen have been shown to be poor inducers of interleukin (IL)-2 production by CD8 T cells when compared to the CD8 super(-) DC. As a consequence, CD8 T cells give a more prolonged proliferative response to CD8 super(-) DC than to CD8 super(+) DC. The possible mechanisms underlying these functional differences in DC subtype have been investigated. Inadequate co-stimulation did not underlie the poor T cell response to allogeneic CD8 super(+) DC. Equivalent levels of B7-1 (CD80) and B7-2 (CD86) were found on the two DC subtypes and co-stimulator assays did not reveal any functional differences between them. Although CD8 super(+) DC were found to die more rapidly in culture than CD8 super(-) DC, this did not explain their reduced stimulatory 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 addition to the cultures of DC of the opposite type to the initiating DC did not reverse or eliminate the differential response to the initiating DC. The role of DC-derived soluble factors was examined by addition to the cultures of supernatants derived from freshly isolated or stimulated DC of the opposite type. This neither enhanced the poor stimulatory capacity of CD8 super(+) DC nor inhibited the stimulation by CD8 super(-) DC. Furthermore, addition of a series of cytokines that might have been produced by the DC did not eliminate the differences in T cell proliferation. 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 difference in the response of CD8 T cells to CD8 super(+) and CD8 super(-) DC is therefore determined by direct DC-T cell contact during the earliest stages of the culture and involves an undetermined and possibly new signaling system.