Steady-state Langerhans cells induce Tfh and B cell responses through a type I interferon and IL-6 independent mechanism

Abstract

Langerhans cells (LCs) can support the induction of antibody responses against foreign antigens without a danger signal. These findings contradict the danger model proposed to define how the adaptive immune responses are mounted. Deciphering how LCs, and some other dendritic cell subsets, support adaptive immune responses in steady-state could lead to a better understanding of how immune responses are induced and regulated and, ultimately, to developing more efficient immunotherapeutics for autoimmune- and infectious diseases. Here we used a well-established steady-state antigen targeting model to dissect the mechanism by which LCs support T follicular helper (Tfh) cells and antibody responses. Using bone marrow chimeras, Cre-lox system, and blocking antibodies, we found that IL-6, which is critical in the induction of Tfh cells and antibody responses in inflammatory conditions, played no role in LC-induced adaptive immune responses at steady-state. Type I interferon signaling was also dispensable in this regard. However, our preliminary data support that induction of humoral immune responses by steady-state LCs depends on membrane-bound co-stimulatory molecules, such as ICOS/ICOS-L. Thus, these data suggest that adaptive immune responses against foreign antigens in the absence of inflammation are generated through a distinct mechanism that likely does not involve inflammatory cytokines. Supported by grants from NIH R01AI146420 and Thomas Jefferson University startup funds.