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Secretion by CD4+ T Cells in the Absence of TCR Ligation1
University of Montreal, Allergy Research Laboratory, Louis-Charles Simard Research Center, Notre-Dame Hospital, Montreal, Canada
At inflammatory sites, the number of activated bystander T cells
exceeds that of Ag-activated T cells. We investigated whether IL-15, a
monocyte-derived cytokine that shares several biologic activities with
IL-2, may contribute to bystander T cell activation in the absence of
IL-2 and triggering Ag. The addition of IL-15 to cocultures of
monocytes and T cells stimulates CD4+ but not
CD8+ T cells to produce IFN-
. IFN- production
requires endogenous IL-12, the production of which in turn is dependent
upon CD40/CD154 interactions between CD4+ T cells and
monocytes. Indeed, non-TCR-activated CD4+ but not
CD8+ T cells express significant levels of CD154. IL-15 may
enhance IFN- in this system by up-regulating CD40 expression on
monocytes and IL-12Rß1 expression on CD4+ T cells.
Conversely, using neutralizing anti-IL-15 mAb, we show that the
ability of IL-12 to augment IFN- secretion is partly mediated by
endogenous IL-15. Finally, in the absence of monocytes, a synergistic
effect between exogenous IL-12 and IL-15 is necessary to induce IFN-
production by purified CD4+ T cells, while IL-15 alone
induces T cell proliferation. It is proposed that this codependence
between IL-12 and IL-15 for the activation of inflammatory T cells may
be involved in chronic inflammatory disorders that are dominated by a
Th1 response. In such a response, a self-perpetuating cycle of
inflammation is set forth, because IL-15-stimulated CD4+ T
cells may activate monocytes to release IL-12 that synergizes with
IL-15 to induce IL-12 response and IFN-
production.
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