Distinct fates of self-specific T cells developing in irradiation bone marrow chimeras: clonal deletion, clonal anergy, or in vitro responsiveness to self-Mls-1a 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-1a-specific V beta 6+ T lymphocyte is controlled by a radiosensitive I-E+ thymic component. Irradiation chimeras reconstituted with I-E- bone marrow showed substantial numbers of mature V beta 6+ T cells despite host Mls-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 V beta 6+ 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 V beta 6+ cells were highly responsive to Mls-1a in vitro. These findings suggest that clonal anergy of V beta 6+ 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 V beta 6+ cells did not differ clinically from those with anergic or deleted V beta 6+ 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.
Speiser
D E
DE
Ludwig Institute for Cancer Research, Epalinges, Switzerland.
Chvatchko
Y
Y
Zinkernagel
R M
RM
MacDonald
H R
HR
D000818:Animals; D001853:Bone Marrow / Q000502:physiology / Q000528:radiation effects; D001854:Bone Marrow Cells; D016026:Bone Marrow Transplantation; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002999:Clone Cells / Q000166:cytology*; D006239:Haplotypes; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology / Q000502:physiology; D006579:Heterozygote; D006720:Homozygote; D007376:Interleukin-2 / Q000494:pharmacology; D016131:Lymphocyte Subsets; D008285:Major Histocompatibility Complex / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains / Q000235:genetics*; D011828:Radiation Chimera; D013601:T-Lymphocytes / Q000166:cytology* / Q000502:physiology / Q000528:radiation effects; D013950:Thymus Gland / Q000166:cytology / Q000502:physiology / Q000528:radiation effects
D007376:Interleukin-2