Ontogeny of Th1 Memory Responses against aBrucella abortusConjugate

Naive T helper cells can differentiate into one of two subsets, known as Th1 or Th2, depending on the context of the initial stimulation they receive (10). In the presence of interleukin-12 (IL-12) Th1 cells, which secrete IL-2, gamma interferon (IFN-γ), and tumor necrosis factor beta (TNF-β), develop. On the other hand, induction of IL-4 favors the development of Th2 cells, which produce IL-4, IL-5, IL-6, IL-10, and IL-13 (11, 25). Antibody class switching in the mouse is influenced by T-cell cytokines such that IFN-γ promotes secretion of immunoglobulin G2a (IgG2a) antibodies, and IL-4 promotes secretion of IgG1 and IgE (1, 4). T-cell subsets are also capable of cross-regulation: IFN-γ inhibits the actions of IL-4 on resting B cells, including secretion of IgE and IgG1 isotypes (18). IL-4, on the other hand, down-regulates the secretion of IFN-γ by CD4+ T cells (14). Antigen-specific responses have not been studied in detail at early stages of immune development. Host protection against intracellular infections, such as Brucella abortus infections, involves a Th1-like response (9). Heat-killed B. abortus (HKBA) has been shown to up-regulate the secretion of IL-12 and IFN-γ (2, 12, 21) and is considered a strong Th1 stimulus (2, 19). We have recently demonstrated that a single injection of B. abortus, when injected together with ovalbumin adsorbed to alum (OVA-A) into adult mice, has the ability to abolish antigen-specific IgE-mediated allergic responses to repeated OVA-A challenge and to increase production of IgG2a in vivo (12, 13). This effect of B. abortus on isotype switching correlated with an increase in IFN-γ and a decrease in IL-4-secreting-cells (12). Thus, B. abortus has the ability to alter the antigen-specific cytokine profile from Th2- to Th1-like when injected together with OVA-A in adult mice. This has implications for mounting effective immune responses against B. abortus, as well as enabling B. abortus to be used as a vaccine adjuvant or carrier in situations where Th1 reactivity is beneficial. In this report we examine the ontogeny of this Th1-to-Th2 switch in young mice using OVA conjugated to HKBA (HKBA-OVA) as a Th1 stimulus. The results have implications for immunization and protection against bacterial infections. In addition, they provide insights into approaches that could prevent allergic disease.