Sustained signaling by canonical helper T cell cytokines throughout the reactive lymph node

Cytokine signaling is thought to be tightly localized in lymphoid tissues. Mohrs and co-workers show that interferon-γ and interleukin 4 signal to most lymphocytes throughout the reactive lymph node. Cytokines are soluble proteins that regulate immune responses. The present paradigm is that cytokine production in lymphoid tissues is tightly localized and signaling occurs between conjugate cells. Here we assess cytokine signaling during infection by measuring in vivo phosphorylation of intracellular signal transducer and activator of transcription (STAT) proteins. We show that interferon-γ (IFN-γ) and interleukin 4 (IL-4) signaled to the majority of lymphocytes throughout the reactive lymph node and that IL-4 conditioning of naive, bystander cells was sufficient to override opposing T helper type 1 (T H 1) polarization. Our results demonstrate that despite localized production, cytokines can permeate a lymph node and modify the majority of cells therein. Cytokine conditioning of bystander cells could provide a mechanism by which chronic worm infections subvert the host response to subsequent infections or vaccination attempts.