T-cell tolerance: exposure to virus in utero does not cause a permanent deletion of specific T cells.

Abstract

This study documents the curing of a congenitally acquired chronic viral infection and the acquisition of T-cell competence by a previously tolerant host. Infection of mice with lymphocytic choriomeningitis virus (LCMV) is a classic model of viral persistence and antigen-specific T-celi unresponsiveness. Mice infected at birth or in utero become lifelong carriers with no detectable virus-specific cytotoxic T lymphocyte (CTL) responses. This chronic infection can be eliminated by adoptive transfer of Lyt-2+ T cells from LCMVimmune mice. To determine whether these cured carriers were capable of generating their own LCMV-specific CTL response, mice congenic at the Thy-i locus (Thy-1.1 and Thy-1.2) were used in the adoptive transfer experiments. Hostderived T-cell responses were checked after treating the cured carriers with a monoclonal antibody to deplete the immune donor T cells. Such cured carrier mice were able to generate a host-derived virus-specific CTL response and resisted a second LCMV challenge in the absence of any donor T cells. In addition, bone marrow cells from these cured carriers could functionally reconstitute irradiated mice. Thus this report demonstrates the acquisition of LCMV-specific T-cell competence by previously unresponsive carrier mice infected in utero. These results show that exposure to a virus even during embryonic life does not cause a permanent deletion of specific T cells. These findings are of significance to the understanding of tolerance mechanisms and have implications for the treatment of chronic viral infections.Congenitally acquired chronic infection of mice with lymphocytic choriomeningitis virus (LCMV) is a classic model of immunological tolerance and viral persistence. The prediction of Burnet and Fenner (1) that an antigen introduced into the body during embryonic life would be mistaken for self, and Burnet's (2) theory of clonal deletion of self-reactive clones, were partly based on Traub's (3) studies on congenital infection of mice with LCMV. The other finding that led Burnet and Fenner to postulate the concept of immunological tolerance to antigens encountered during ontogeny was Owen's (4) observations that dizygotic cattle twins sharing vascular supplies in utero developed into erythrocyte chimeras.Mice infected with LCMV at birth or in utero become lifelong carriers, with high levels of infectious virus in most of their organs. Although such persistently infected mice make virus-specific antibody responses (5), attempts by several investigators to demonstrate virus-specific T cells have been mostly unsuccessful (6-11). These carrier mice show minimal or no detectable cytotoxic-T-lymphocyte (CTL) or delayedtype-hypersensitivity (DTH) responses against LCMV, and they also show either a paucity or a lack of T cells that will proliferate when stimulated with the virus. In this study, we demonstrate the acquisition of T-cell competence in mice cured of congenitally acquired chronic LCMV infection. The cured carrier mice can generate a host-derived-virus-spec...

Persistence of Physiological Self Antigen Is Required for the Regulation of Self Tolerance

“…Thus, persistent alloantigen was required for maintenance of the experimental adult tolerance. A similar requirement for Ag persistence has been demonstrated for maintaining T cell tolerance to foreign proteins (32,33), peptide (34), and virus (35). Additional studies reached a similar conclusion by "parking" tolerized T cells in an immunodeficient host that lacked the tolerogen and demonstrating that the T cells regained the ability to respond to the nominal Ag (36 -38).…”

Enhanced Type 1 Immunity After Secondary Viral Challenge in Mice Primed as Neonates

“…Since an optimal number of splenocytes were transferred in these experiments, we are determining whether transfer of limiting numbers of donor Cas-specific memory cells would reveal a difference in the quality of protection between cells of mice primed in adulthood compared with those primed during the neonatal period. We note that donor cells may control viral replication at least in part by assisting the development of a host-derived immune response (41,42). Nevertheless, our data suggest that the maturity of the neonatal immune response may be underestimated if only based on quantitative differences.…”

An Odyssey to Viral Pathogenesis

“…Further studies revealed that immune complex formation and deposition in selected tissues could be extended to many chronic human viral infections (reviewed in 42) such as hepatitis B virus, cytomegalovirus, Epstein-Barr virus, and later HIV, indicating that immune complexes are signatures of persistent infections. Shortly after we authenticated the lack of B cell tolerance in LCMV infection initiated in utero or at birth, Rafi Ahmed, having left my laboratory for a faculty position at UCLA, showed that the absence of virus-specific T cells (more about that later) in adults persistently infected in utero or at birth did not result from clonal deletion of LCMV-specific T cells but rather was masked by an excess of viral antigen (45).…”