DISTINCT FATES OF SELF-SPECIFIC T-CELLS DEVELOPING IN IRRADIATION BONE-MARROW CHIMERAS - CLONAL DELETION, CLONAL ANERGY, OR INVITRO RESPONSIVENESS TO SELF-MLS-1A CONTROLLED BY HEMATOPOIETIC-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-1a-specific Vγ6+ T lymphocytes is controlled by a radiosensitive I-E+ thymic component. Irradiation chimeras reconstituted with I-E− bone marrow showed substantial numbers of mature Vγ6+ 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-2s) stem cells, mature Vγ6+ lymphocytes were present but functionally anergic to host-type Mls-1a in vitro. In contrast, in chimeras reconstituted with B10.G (H-2q) bone marrow, nondeleted Vγ6+ cells were highly responsive to MIS-1a in vitro. These findings suggest that clonal anergy of Vγ6+ cells to self- Mls-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-1a)-reactive Vγ6+ cells did not differ clinically from those with anergic or deleted Vγ6+ 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-1a. © 1990, Rockefeller University Press., All rights reserved.