Abstract
IL-13 driven Th2 immunity is indispensable for host protection against infection with the gastrointestinal nematode Nippostronglus brasiliensis. Disruption of CD28 mediated costimulation impairs development of adequate Th2 immunity, showing an importance for CD28 during the initiation of an immune response against this pathogen. In this study, we used global CD28−/− mice and a recently established mouse model that allows for inducible deletion of the cd28 gene by oral administration of tamoxifen (CD28−/loxCre+/−+TM) to resolve the controversy surrounding the requirement of CD28 costimulation for recall of protective memory responses against pathogenic infections. Following primary infection with N. brasiliensis, CD28−/− mice had delayed expulsion of adult worms in the small intestine compared to wild-type C57BL/6 mice that cleared the infection by day 9 post-infection. Delayed expulsion was associated with reduced production of IL-13 and reduced serum levels of antigen specific IgG1 and total IgE. Interestingly, abrogation of CD28 costimulation in CD28−/loxCre+/− mice by oral administration of tamoxifen prior to secondary infection with N. brasiliensis resulted in impaired worm expulsion, similarly to infected CD28−/− mice. This was associated with reduced production of the Th2 cytokines IL-13 and IL-4, diminished serum titres of antigen specific IgG1 and total IgE and a reduced CXCR5+ TFH cell population. Furthermore, total number of CD4+ T cells and B220+ B cells secreting Th1 and Th2 cytokines were significantly reduced in CD28−/− mice and tamoxifen treated CD28−/loxCre+/− mice compared to C57BL/6 mice. Importantly, interfering with CD28 costimulatory signalling before re-infection impaired the recruitment and/or expansion of central and effector memory CD4+ T cells and follicular B cells to the draining lymph node of tamoxifen treated CD28−/loxCre+/− mice. Therefore, it can be concluded that CD28 costimulation is essential for conferring host protection during secondary N. brasiliensis infection.
Highlights
CD28 is considered to be the main co-stimulator of T cells, providing a critical signal for activation of naive T cells [1,2,3]
CD28 costimulatory signalling is required for optimal immunity against N. brasiliensis infection In order to investigate whether CD28 is required for the development of protective immunity against N. brasiliensis infection, CD282/2 mice were infected with 500 infective N. brasiliensis larvae and killed 9 and 12 days post-infection (Fig. 1A)
Associated with transiently increased worm burdens in infected CD282/2 mice was the number of mucus producing goblet cells that were reduced at day 9 postinfection in this mouse strain compared to control mice (Fig. 1C)
Summary
CD28 is considered to be the main co-stimulator of T cells, providing a critical signal for activation of naive T cells [1,2,3]. Interactions between CD28 and its ligands CD80/CD86 enhances cytokine production, prevents T cell anergy and protects against apoptosis [4,5] These CD28 dependent interactions are important during the initiation of T cell mediated immunity against a number of infections. CD282/2 mice infected with S. mansoni [6] or Leishmania major [7] failed to produce antigen specific type 2 antibodies IgG1 and IgE. Taken together this demonstrates an important role for CD28 in co-ordinating B cell responses
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