Neonatal Peptide Exposure Can Prime T Cells and, upon Subsequent Immunization, Induce Their Immune Deviation: Implications for Antibody

Neonatal exposure to antigen is believed to result in T cell clonal inactivation or deletion. Here we report that, contrary to this notion, neonatal injection of BALB/c mice with a hen egg lysozyme peptide 106-116 in putative "tolerogenic" doses induced a T cell proliferative and an immunoglobulin G (IgG) antibody (Ab) response of both T helper cell 1 (Thl)(IgG2a, IgG2b, and IgG3) and Th2-dependent (IgG1) isotypes. Upon subsequent challenge with the peptide in complete Freund's adjuvant in adult life, although this neonatal regimen suppressed proliferation and the production of Thl cytokines (interleukin[IL]-2 and interferon ~/), Th2 cytokine (IL-5, IL-4, and IL-10) secretion was increased, and the serum levels of T h l and Th2dependent isotypes of peptide-specific Ab remained elevated. The in vitro proliferative unresponsiveness in Thl cells could be reversed by Abs to Th2 cytokines (IL-4 and IL-10). Thus, neonatal treatment with a peptide antigen induces T cell priming including production of IgG Abs of both T h l and Th2-dependent isotypes. Upon subsequent peptide exposure, the peptide-specific T cell responses undergo an effective class switch in the direction of Th2, resulting in T cell proliferative unresponsiveness. Accordingly, this shift towards increased Ab production to autoantigen could be deleterious in individuals prone to autoantibody-mediated diseases. Indeed, neonatal treatment with a self-autoantigenic peptide from an anti-DNA monoclonal Ab (A6H 58-69) significantly increased the IgG anti-double-stranded DNA Ab levels in lupus-prone N Z B / N Z W F1 mice, despite suppressing peptide-specific T cell proliferation. This adverse clinical response is in sharp contrast to the beneficial outcome of neonatal treatment with autoantigens in Thl-mediated autoimmune diseases, such as autoimmune encephalomyelitis, as reported by others. A Thl to Th2 immune deviation can explain the discordant biological responses after the presumed induction of neonatal tolerance in autoantibodyvs. Thl-mediated autoimmune diseases.