Distinct Fates of Self-specific T Cells Developing in Irradiation Bone Marrow Chimeras: Clonal Deletion, Clonal Anergy, or In Vitro Responsiveness to Self-Mls-la Controlled by Hemopoietic Cells in the Thymus

Elimination of potentially self-reactive T lymphocytes during their maturation in the thymus has been shown to be a major mechanism in accomplishing self-tolerance. Previous reports demonstrated that clonal deletion of self-Mls-l a -specific V,36+ T lymphocytes is controlled by a radiosensitive I-E+ thymic component. Irradiation chimeras reconstituted with I-E bone marrow showed substantial numbers of mature V06+ T cells despite host MIS-1a expression . Analysis of the functional properties of such chimeric T cells revealed a surprising variability in their in vitro reactivity to host Mls-1a, depending on the H-2 haplotype of stem cells used for reconstitution . In chimeras reconstituted with B10.S (H-2') stem cells, mature Va6+ lymphocytes were present but functionally anergic to host-type Mls-1a in vitro. In contrast, in chimeras reconstituted with B10.G (H-29) bone marrow, nondeleted V)36+ cells were highly responsive to MIS-1a in vitro. These findings suggest that clonal anergy of V$6+ cells to selfMls-1a may be controlled by the affinity/avidity of T cell receptor interactions with bone marrow-derived cells in the thymus depending on the major histocompatibility complex class II molecules involved . Furthermore, chimeras bearing host (Mls-la)-reactive V06+ cells did not differ clinically from those with anergic or deleted V06+ cells and survived more than one year without signs of autoimmune disease . Interestingly, their spleen cells had no Mls-1a stimulatory capacity in vitro. Therefore, regulation at the level of antigen presentation may be an alternative mechanism for maintenance of tolerance to certain self-antigens such as Mls-la .