Neonatal peptide exposure can prime T cells and, upon subsequent immunization, induce their immune deviation: implications for antibody vs. T cell-mediated autoimmunity.

Abstract

SummaryNeonatal 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 Thl-and Th2-dependent 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 Thl-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 NZB/NZW 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 autoantibody-vs. Thl-mediated autoimmune diseases.

Induction of neonatal tolerance by plasmid DNA vaccination of mice.

“…Several recent reports challenge the existence of neonatal tolerance, claiming instead that newborns actively mount an immune response against foreign antigens but that their response differs in cytokine and/or antibody profile from that elicited in adults (25,26). Our results do not support such a hypothesis, since pCSP-tolerized mice were unable to mount either Th1 (IFN ␥ ) or Th2 (IL-4) cytokine responses when challenged with pCSP in vitro or in vivo.…”

CD1d deficiency exacerbates inflammatory dermatitis in MRL‐lpr/lpr mice

“…In fact, a recent study described significant acceleration of skin disease in IL-10 KO MRL-lpr mice [37]. IL-10 also plays a critical role in the development of immune tolerance [38]. Thus, IL-10 produced by CD1d-reactive NKT cells may play a role in the development of immune tolerance that can be facilitated by CD1d-reactive NKT cells [39].…”

“…g/ml) or plate-bound anti-CD3 mAb (1-10 ? g/ml) for 48 h. The supernatants were tested for cytokines by ELISA using mAb pairs and recombinant cytokine standards from PharMingen, as described [38].…”

Maternal Autoantibody Triggers De Novo T Cell-Mediated Neonatal Autoimmune Disease

“…Autoimmune gastritis is induced by neonatal injection of the gastric parietal cell H ϩ ,K ϩ -ATPase in water (40). Lupus autoantibody and nephritis develop in mice injected neonatally with a peptide that mimics dsDNA in IFA (41). In addition, tolerance to the alloantigen is preceded by an early and transient graft-vs-host response to the donor MHC class II alloantigen and by a transient lupus-like disease (42) that is greatly amplified in mice with bcl-2-overexpressing B cells (43).…”