Intrathymic and extrathymic tolerance in bone marrow chimeras

Area of Science:

• Immunology
• Transplantation Immunology
• T cell tolerance

Background:

• Parent-->F1 bone marrow chimeras are models for studying self-tolerance induction.
• Host H-2 antigen expression in chimeras is limited to non-bone marrow-derived cells.

Purpose of the Study:

• To investigate the mechanisms of self-tolerance induction in parent-->F1 bone marrow chimeras.
• To determine if host H-2 antigens in the post-thymic environment are tolerogenic for mature T cells.

Main Methods:

• Preparation of parent-->F1 bone marrow chimeras using supralethal irradiation and anti-T cell antibodies.
• Injection of parental strain T cells into chimeras.
• Analysis of T cell responses, including proliferation, differentiation, and cytotoxic T lymphocyte (CTL) precursor frequency.
• Grafting of parental strain thymus into thymectomized chimeras.

Main Results:

• Expression of host H-2 antigens in the post-thymic environment did not induce tolerance in injected T cells.
• Tolerance was observed when parental strain T cells differentiated in the endogenous thymus of chimeras.
• Cytotoxic T lymphocyte (CTL) precursors generated in the thymus showed increased tolerance in lymph nodes compared to the thymus.
• Intrathymic exposure to host antigens on thymic epithelial cells (TEC) rendered CTL precursors "semi-tolerant".

Conclusions:

• Host H-2 antigens in the extrathymic environment are not intrinsically tolerogenic for mature T cells.
• Tolerance induction occurs primarily during T cell differentiation within the endogenous thymus.
• A covert form of tolerance induced in the thymus leads to peripheral deletion of semi-tolerant T cells.
• High-affinity T cells may control graft-versus-host disease, while typical CTLs are predominantly low-affinity cells.