Langerhans Cells Drive Tfh and B Cell Responses Independent of Canonical Cytokine Signals

Dendritic cells (DCs) are key regulators of adaptive immunity, guiding T helper (Th) cell differentiation through antigen presentation, co-stimulation, and cytokine production. However, in steady-state conditions, certain DC subsets, such as Langerhans cells (LCs), induce T follicular helper (Tfh) cells and B cell responses without inflammatory stimuli. Using multiple mouse models and in vitro systems, we investigated the mechanisms underlying steady-state LC-induced adaptive immune responses. We found that LCs drive germinal center Tfh and B cell differentiation and antibody production independently of interleukin-6 (IL-6), type-I interferons, and ICOS ligand (ICOS-L) signaling, which are critical in inflammatory settings. Instead, these responses relied on CD80/CD86-mediated co-stimulation. Our findings challenge the conventional three-signal paradigm by demonstrating that cytokine signaling is dispensable for LC-mediated Tfh and B cell responses in steady-state. These insights provide a framework for understanding homeostatic immunity and the immune system’s role in maintaining tolerance or developing autoimmunity under non-inflammatory conditions.