Intradermal immunization in the ear with cholera toxin and its non‐toxic β subunit promotes efficient Th1 and Th17 differentiation dependent on migrating DCs

Abstract

The nature of CD4 1 T-cell responses after skin immunization and the role of migrating DCs in the presence of adjuvants in the elicited response are interesting issues to be investigated. Here, we evaluated the priming of CD4 1 T cells following ear immunization with low doses of model antigens in combination with either cholera toxin (CT) or the non-toxic b CT subunit (CTB) as an adjuvant. Following immunization with CT, we found efficient antigen presentation that is reflected in the production of IFN-c and IL-17 by CD4 1 T cells over IL-4 or IL-5 production. The CTB-induced activation of DCs in the ear occurred without visible inflammation, which reflects a similar type of CD4 1 T-cell differentiation. In both cases, the elicited response was dependent on the presence of migrating skin cells. Remarkably, immunization with CT or with CTB led to the induction of a delayed-type hypersensitivity (DTH) response in the ear. The DTH response that was induced by CT immunization was dependent on IL-17 and partially dependent on IFN-c activity. These results indicate that both CT and CTB induce an efficient CD4 1 T-cell response to a co-administered antigen following ear immunization that is dependent on migrating DCs.Key words: DCs . Migrating DCs . Skin immunization Supporting Information available online IntroductionThe skin is the first line of defense against microbial pathogens. There is supporting evidence that DCs are crucial for the initiation, polarization and control of the adaptive immune response [1,2]. Efficient immunosurveillance in the skin is based upon the continuous traffic of cells from the skin to the draining lymph nodes. Although Langerhans cells (LCs) have been shown to be potent APCs in vitro [3], in vivo approaches have produced conflicting data regarding their role in T-cell priming [4,5]. Dermal DCs are also migrating DCs that colonize lymph nodes more rapidly than LCs [6,7], and different roles for skin DC subsets in T-cell priming have been reported [7][8][9]. Skin immunization has yielded controversial data, with some reports supporting a Th2-type response [10,11] and others a Th1-type response [12,13]. IL-17-producing CD4 1 T cells (Th17) have also been found after skin immunization [13,14]. 2894Cholera toxin (CT) has a strong adjuvant effect [15]. When administered in the mucosa, CT can elicit a Th2-type response that is based on the production of IL-4, IL-5 and IL-10 but virtually no 17]. However, a mixed Th1/Th2 response that produces both IFN-g and IL-4 has also been observed [18], and the administration of ovalbumin (OVA) in combination with CT elicits a dominant Th17 response following intranasal immunization [19]. This dominance of IL-17 was also observed in response to the CT b subunit (CTB). Although the precise mechanism for the adjuvant effect of CT is not completely understood, it appears that CTB targets DCs in vivo by binding to the cell membrane ganglioside GM1 [20]; moreover, the CT a subunit (CTA) triggers the PKA-mediated induction of cAMP, which plays a critical role ...

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