T Cells Undergo Rapid ON/OFF but Not ON/OFF/ON Cycling of Cytokine Production in Response to Antigen

Abstract

Inflammatory cytokines such as IFN-γ and TNF produced by Ag-stimulated CD4+ and CD8+ T cells are important in defense against microbial infection. However, production of these cytokines must be tightly regulated to prevent immunopathology. Previous studies, conducted with BALB/c mice, have suggested that 1) CD8+ T cells maintain IFN-γ production but transiently produce TNF in the continued presence of Ag and 2) lymphocytic choriomeningitis virus-specific and in vitro-propagated effector CD8+ T cells could rapidly cycle IFN-γ production ON/OFF/ON in response to Ag exposure, removal, and re-exposure. In contrast with CD8+ T cells, our results show that Listeria monocytogenes-specific CD4+ T cells from C57BL/6 mice rapidly initiate (ON cycling) and maintain production of both IFN-γ and TNF in the continued presence of Ag. Upon Ag removal, production of both cytokines rapidly ceases (OFF cycling). However, if the initial stimulation was maximal, Ag-specific CD4+ T cells were unable to reinitiate cytokine production after a second Ag exposure. Furthermore, L. monocytogenes-specific CD8+ T cells in the same mice and lymphocytic choriomeningitis virus-specific CD8+ T cells in BALB/c mice also underwent ON/OFF cycling, but if the initial Ag stimulus was maximal, they could not produce IFN-γ after Ag re-exposure. As the initial Ag dose was reduced, the number of cells producing cytokine in response to the second Ag exposure exhibited a corresponding increase. However, T cells that were marked for IFN-γ secretion during the first stimulation did not contribute cytokine production during the second stimulation. Thus, T cells are not able to undergo rapid ON/OFF/ON cytokine cycling in vitro in response to Ag.