IL-4Rα-Associated Antigen Processing by B Cells Promotes Immunity in Nippostrongylus brasiliensis Infection

Abstract

In this study, B cell function in protective T _H2 immunity against N. brasiliensis infection was investigated. Protection against secondary infection depended on IL-4Rα and IL-13; but not IL-4. Protection did not associate with parasite specific antibody responses. Re-infection of B cell-specific IL-4Rα ^−/− mice resulted in increased worm burdens compared to control mice, despite their equivalent capacity to control primary infection. Impaired protection correlated with reduced lymphocyte IL-13 production and B cell MHC class II and CD86 surface expression. Adoptive transfer of in vivo N. brasiliensis primed IL-4Rα expressing B cells into naïve BALB/c mice, but not IL-4Rα or IL-13 deficient B cells, conferred protection against primary N. brasiliensis infection. This protection required MHC class II compatibility on B cells suggesting cognate interactions by B cells with CD4 ⁺ T cells were important to co-ordinate immunity. Furthermore, the rapid nature of these protective effects by B cells suggested non-BCR mediated mechanisms, such as via Toll Like Receptors, was involved, and this was supported by transfer experiments using antigen pulsed Myd88 ^−/− B cells. These data suggest TLR dependent antigen processing by IL-4Rα-responsive B cells producing IL-13 contribute significantly to CD4 ⁺ T cell-mediated protective immunity against N. brasiliensis infection.

Author Summary

Parasitic nematode infections are an extremely important global public health problem. Infections by hookworms and roundworms for example cause anemia, widespread developmental problems and devalued immunity against bacterial infections such as salmonella and tuberculosis. Although treatable with drugs, parasitic nematode re-infections occur as humans do not develop protective immunity. Ultimately, the public health burden caused by these infections will be best controlled by the development of vaccines against nematode infections. For these to be effective, it is important to understand how the various components of the immune system can respond to infection. In this study, we show that B cells, which typically protect against infection by producing antibodies, can also protect against an experimental hookworm like nematode infection by additional mechanisms. This form of protection instead depended on B cells producing cytokines associated with parasitic nematode expulsion and also by providing T cells with specific instruction. Together, these B cell driven responses lead to a rapid resolution of the infection. These important findings indicate that vaccination strategies against nematode parasites such as hookworms need to understand immune responses other than antibody to be optimally protective.