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.
Highlights
Understanding the interplay of cellular and molecular factors involved in induction and regulation of adaptive immune responses is crucial to promote diverse areas of medicine including control of infectious disease, vaccine development, and immunotherapy of cancer
As mucosal Mast cell (MC) of the intestinal tract can be metachromatically stained using special fixation procedures like Carnoy fixation but not after formalin fixation, we performed additional Giemsa staining of Carnoy-fixed skin to exclude the presence of skin MC populations that fail to stain with conventional protocols (Figure S1 in Supplementary Material) and confirmed near complete absence of MCs in the skin of Mcpt5-Cre ROSA26-DTA knock in allele (R26DTA)/diphtheria toxin A (DTA) mice
Saline injected animals served as controls. 24 h after infection, the E. coli-injected Cre-negative controls displayed a substantial increase in popliteal LN size and total cellularity with increased numbers of T cells, B cells, and Dendritic cells (DCs) compared with the saline injected group as expected (Figure 1A)
Summary
Understanding the interplay of cellular and molecular factors involved in induction and regulation of adaptive immune responses is crucial to promote diverse areas of medicine including control of infectious disease, vaccine development, and immunotherapy of cancer. Dendritic cells (DCs), the most important antigen-presenting cells, represent the central switch controlling T cell, and thereby B cell responses. DCs reside in peripheral tissues where they sample their environment. They sense microbial infection by means of pattern-recognition receptors (PRRs) which detect microbial structures [pathogen-associated molecular patterns (PAMPs)] as well as molecular changes. DCs integrate PRR signals and, depending on the outcome of this process, migrate to draining LNs, upregulate their antigen-presentation machinery and increase expression of co-stimulatory molecules and cytokines, thereby providing essential signals for T cell activation and differentiation in the LN. The intensity and quality of PRR and cytokine signals the DC received in the tissue determines intensity and quality of the T cell response it drives in the LN [1]
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