Unimpaired Responses to Vaccination With Protein Antigen Plus Adjuvant in Mice With Kit-Independent Mast Cell Deficiency

Abstract

Innate inflammatory responses are crucial for induction and regulation of T cell and antibody responses. Mast cell (MC)-deficient Kit mutant mice showed impaired adaptive immunity, suggesting that MCs provide essential adjuvant activities, and pharmacological MC activation was proposed as a new adjuvant principle. However, the Kit mutations result in complex alterations of the immune system in addition to MC deficiency. We revisited the role of MCs in vaccination responses using Mcpt5-Cre R26DTA/DTA and Cpa3Cre/+ mice that lack connective tissue MCs or all MCs, respectively, but feature an otherwise normal immune system. These animals showed no impairment of T and B cell responses to intradermal vaccination with protein antigen plus complete Freund’s adjuvant. Moreover, we demonstrate that the adjuvant effects of the MC secretagogue c48/80 in intradermal or mucosal immunization are independent of the presence of MCs. We hence find no evidence for a regulation by MCs of adaptive immune responses to protein antigens. The finding that immunological MC functions differ from those suggested by experiments in Kit mutants, emphasizes the importance of rigorous tests in Kit-independent MC-deficiency models.

Mast cells drive IgE-mediated disease but might be bystanders in many other inflammatory and neoplastic conditions

“…Mcpt5-Cre R26 DTA mice were devoid of CTMCs but retained MMCs and a small population of lymph node MCs. 59,61 IgE-mediated responses were undetectable. 53 Mcpt5-Cre mice were also crossed to Dicer FL/FL mice to inactivate microRNA processing in MCs, 62 resulting in almost complete absence of CTMCs and IgE-dependent responses.…”

Mast Cell Functions Linking Innate Sensing to Adaptive Immunity

“…In MC-deficient Kit mutant mice, an impaired protective humoral response to E. coli was observed, which led to the suggestion of pharmacologic MC activation as a new adjuvant principle in vaccination [72,113,114]. However, a non-redundant role for MCs in antibody production could not be confirmed in Kit independent novel mouse models of MCdeficiency [115].…”

“…In vitro, naïve, sensitized and activated MCs were shown to promote proliferation of naïve and B cell receptor-activated B cells [116][117][118], as well as both follicular and marginal zone B cells [115]. As indicated by the secretion of IgM and IgG by IgM + B cells, MCs can induce class switch recombination [115].…”

“…In vitro, naïve, sensitized and activated MCs were shown to promote proliferation of naïve and B cell receptor-activated B cells [116][117][118], as well as both follicular and marginal zone B cells [115]. As indicated by the secretion of IgM and IgG by IgM + B cells, MCs can induce class switch recombination [115]. Pucillo and colleagues further reported that the CD40/CD40Lmediated MC/B cell contact, together with IL-6 secretion by MCs differentiates B cells to CD138 + plasma cells and IgA secretion [114].…”

Mast cells within cellular networks

“…Of note, adjuvant effects of compound 48/80 applied either intradermally or through the mucosal route were recently shown to be independent of mast cells by using Kit-independent mast celldeficient mouse strains. 76 Murine inflammatory airway disease based on sensitization to antigens and subsequent provocation is often used as a model for the pathogenesis of human asthma, including inflammation of the airways, overproduction of mucus, and hyperreactivity to bronchoconstrictors. 77 Mast cells have been linked to induction of allergic airway disease in mice, although this was shown to depend on the experimental model.…”