Modulation of cellular and humoral immune response to third party antigens in nematode-infected mice

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One third of the human population is infected with helminth parasites. To avoid their expulsion and to limit pathology, helminths have developed sophisticated strategies to suppress and modulate the immune response of their hosts. As this immune suppression spills over to unrelated third-party antigens, a preexisting helminth infection may interfere with vaccination efficacy. We have shown before that transient infection of mice with Strongyloides ratti induced a diversion of antibody responses to model antigen vaccination towards a type 2 phenotype whereas a long lasting infection with Litomosoides sigmodontis led to a generalized suppression of all types of antibody responses. The observed suppression of antibody response was not mediated by direct interference with antibody-producing B cells but predominantly by interference with T helper cell function. In the current application we will use L. sigmodontis-infected mice to elucidate the molecular mechanisms leading to nematode-induced interference with T cell function and T cell dependent B cell responses. In the first part of this application we focus on modulated antibody response during nematode infection. We intend to compare the antibody response to model antigen vaccination in mice at different stages of L. sigmodontis infection, after spontaneous clearance of infection and after drug induced abortion of infection. We intend to search for adjuvants that render vaccinations functional despite a preexisting L. sigmodontis infection and we will analyze the phenotype of follicular T helper cells in detail. In the second part of this application we focus on the modulated T cell response during nematode infection. We will compare the proliferation and the effector functions of adoptively transferred T cell receptor transgenic ovalbumin-specific CD4+ T helper cells (OT-II) and CD8+ cytotoxic T cells (OT-I) within naïve and L. sigmodontis infected mice. Thereby we intend to analyze the role of regulatory cytokines, regulatory receptors and regulatory cell populations in the mediation of nematode-induced T cell suppression. In conclusion we expect to unravel the chain of events leading from established nematode infection to reduced vaccination efficacy. Based on the information gained, we intend to develop vaccination regimes that are functional on the background of preexisting helminth infections in the mouse model. These results may also be useful to develop functional vaccinations for the human population in helminth endemic areas.