| Description |
The activation of CD4+ T cells is controlled via three distinct signals: TCR recognition of the peptide:MHCII complex, coactivation via ligands and receptors expressed on antigen-presenting cells and the T cell, and Signal 3 cytokine signaling. It is this third signal that leads to initial differentiation into the multiple T helper subsets such as Th1, Th2, Th17, and Treg. While the role of Signal 3 cytokines is well-defined in programming differentiation after activation of naïve T cells, their effects on memory CD4+ T cell responses have not been extensively studied. Here we show that interruption of cytokine signaling during secondary CD4+ T cell responses alters their effector function. These effects are independent of TCR affinity for antigen, demonstrating a critical role for appropriate cytokine signaling in the successful production of robust secondary CD4+ T cell responses. During secondary challenge with Listeria monocytogenes, CD4+ T cell responses are differentially regulated by Type I IFN (IFN-I) and IL-12. Effector function is depressed in the presence of IFN-I signaling, while IL-12 promotes the differentiation of highly functional secondary effector cells. Additionally, the mechanisms of regulation by both cytokines may intersect, as IFN-I inhibits the production of IL-12 as well as IFNγ, a critical cytokine for Th1 responses and bacterial clearance. Expansion kinetics are also controlled via these cytokines, with IL-12 promoting robust initial expansion and IFN-I inhibiting expansion but required for limiting contraction during memory formation. Importantly, memory CD4+ T cells alone are able to mediate significant protection from heterologous secondary challenge with Listeria. This protection is entirely dependent upon TNF, as neutralization of this cytokine results in complete loss of CD4+ memory T cell-mediated protection. Surprisingly, IFNγ is not required for protection mediated by secondary effector CD4+ T cells in this setting, though it is required for protection from primary challenge with Listeria. Rather, TNF-dependent differentiation of secondary effector Th1 cells drives increased classical macrophage activation, leading to more rapid bacterial clearance. Together, we demonstrate an important role for cytokine signaling in determining the strength of the secondary response of CD4+ T cells, which can directly influence the protective capacity of these memory cells depending on the type of infection. |
