Ontogeny of T cell tolerance to peripherally expressed antigens - PubMed (original) (raw)

Ontogeny of T cell tolerance to peripherally expressed antigens

D J Morgan et al. Proc Natl Acad Sci U S A. 1999.

Abstract

Transgenic expression of the influenza virus hemagglutinin (HA) in the pancreatic islet beta cells of InsHA mice leads to peripheral tolerance of HA-specific T cells. To examine the onset of tolerance, InsHA mice were immunized with influenza virus A/PR/8 at different ages, and the presence of nontolerant T cells was determined by the induction of autoimmune diabetes. The data revealed a neonatal period wherein T cells were not tolerant and influenza virus infection led to HA-specific beta cell destruction and autoimmune diabetes. The ability to induce autoimmunity gradually waned, such that adult mice were profoundly tolerant to viral HA and were protected from diabetes. Because cross-presentation of islet antigens by professional antigen-presenting cells had been reported to induce peripheral tolerance, the temporal relationship between tolerance induction and activation of HA-specific T cells in the lymph nodes draining the pancreas was examined. In tolerant adult mice, but not in 1-week-old neonates, activation and proliferation of HA-specific CD8(+) T cells occurred in the pancreatic lymph nodes. Thus, lack of tolerance in the perinatal period correlated with lack of activation of antigen-specific CD8(+) T cells. This work provides evidence for the developmental regulation of peripheral tolerance induction.

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Figures

Figure 1

Figure 1

Insulitis in neonatal InsHA mice immunized with PR8. Neonatal InsHA mice at various ages as shown were immunized i.p. with 1,200 HA units of PR8. Shown are immunohistological analyses of pancreata taken from various InsHA mice immunized with PR8. Paraffin-embedded sections are stained for insulin by using the immunoperoxidase technique with diaminobenzidine as a chromagen and counterstained with hematoxylin. (A) Tissue isolated from 1-week-old neonate 9 days after immunization with PR8. Note the overwhelming presence of mononuclear cells, arrows indicate edges of islet remnants leaving only a few insulin positive β cells. (B) One-week-old neonate 9 days after immunization with EqPR8. Islet is free from mononuclear infiltration and uniform insulin staining shows there is no β cell destruction. (C) Two-week-old and (D) 4-week-old mice 9 days after immunizing with PR8, both show considerable insulitis and β cell destruction (arrows). Mice from the same groups, 2 weeks old (F) and 4 weeks old (G), 21 days after immunization. The extent of insulitis and β cell destruction is less at this time (arrows). (E) Representative of the most severe insulitis demonstrated in 8-week-old adult mice 9 days after immunization with PR8. Only a mild peri-insulitis is observed that is not associated with any β cell destruction (arrows). (H) Representative of >90% of islets from these same adults 21 days after immunization. They are intact and express high levels of insulin. Magnifications: A, ×100; B, D, and H, ×400; C and E_–_G, ×200.

Figure 2

Figure 2

CSFE-labeled, purified clone-4 TCR CD8+ T cells do not proliferate in the pancreatic lymph nodes after adoptive transfer into neonatal InsHA mice. Adult InsHA negative (A_–_C) and adult InsHA positive (D_–_F) mice were injected i.v., and 5-day-old neonatal InsHA mice (G and H) were injected i.p. with 5 × 106 CSFE-labeled, purified clone-4 TCR CD8+ T cells. Seventy-two hours later cells isolated from various peripheral lymphoid organs as shown were stained with phycoerythrin-conjugated anti-CD8 antibodies. Data show amount of CSFE label among activated CSFE-labeled CD8+ T cells obtained from pooled lymphoid tissue taken from at least three adult mice per group and seven neonates. For clarity of depiction, the unlabeled cells have been deleted from the histograms.

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