Humoral immunity to Toxoplasma gondii is mediated by the expression of Nfkbid in T cells

The immunological mechanisms underlying the development of a protective immune response against parasitic diseases through vaccination remain unclear. Toxoplasma gondii is a parasite that excels in evading vaccine-induced immunity. Strong CD8⁺ T cell responses with IFNγ production are required to generate a protective immune response. However, the contribution of B cell responses to T. gondii immunity is less understood. Through genetic mapping, we recently reported that Nfkbid, a gene that encodes IκBNS, a member of the atypical family of NF-κB regulators, was required for humoral immunity to T. gondii, with contributions from both conventional B-2 and innate-like B-1 B cells. However, it is unclear which cell populations must express Nfkbid to elicit an effective humoral response to T. gondii. To test the contribution of the Nfkbid expression by T cells, we created a conditional knockout that deletes Nfkbid exclusively in T cells using the Cre-LoxP system. We infected B6.CD4^CreNfkbid^-/- and B6.CD4wtNfkbid^fl/fl with the low virulence type III CEP strain, and after 35 days, during the chronic phase of the infection, we challenged the mice with the type I RH strain. We observed that 100% of B6.CD4^CreNfkbid^-/- (n=6) succumbed to the virulent challenge while all B6.CD4^wtNfkbid^fl/fl (n=5) survived. While no differences were observed in T cell memory subpopulations, we observed a reduction in Tfh and B-1 cells, accompanied by a strong reduction of parasite-specific IgG isotypes and IgM in B6.CD4Nfkbid^-/-, phenocopying our previous observations in Nfkbid^-/- mice. Altogether, these results suggest that in the context of T. gondii, Nfkbid modulates the profound interplay between CD4⁺ and B cells, directly affecting humoral responses to T. gondii. Because follicular helper T cell (Tfh) differentiation promotes IgG responses to model antigens by their CXCR5-dependent entry into the germinal center, we hypothesize that Nfkbid deletion will mainly regulate Tfh cells, resulting in a loss of anti-T. gondii antibody response by B cells, an effect currently being investigated in our laboratory.