Primary and secondary immunocompetence in mixed allogeneic chimeras

Area of Science:

• Immunology
• Transplantation immunology
• Viral immunology

Background:

• Minimally myeloablative strategies target T cell costimulatory pathways (CD28, CD40) to induce mixed allogeneic chimerism and tolerance.
• Mixed allogeneic chimerism involves donor and host immune cell populations.

Purpose of the Study:

• To analyze antiviral CD4 and CD8 responses (host- and donor-restricted) in mixed allogeneic chimeras.
• To assess the impact of mixed chimerism on pre-existing memory T cell populations.
• To investigate the mechanisms of donor-restricted T cell selection.

Main Methods:

• Induction of mixed allogeneic chimerism in two mouse strain combinations.
• Challenge with acute lymphocytic choriomeningitis virus (LCMV) Armstrong or vaccinia virus.
• Challenge with chronic LCMV clone 13.
• Analysis of host- and donor-restricted CD4 and CD8 T cell responses.
• Assessment of pre-existing memory T cell populations.

Main Results:

• Antiviral CD8 responses were largely host-restricted, but donor-restricted CD8 and host/donor-restricted CD4 responses were detected, leading to prompt viral clearance in acute infections.
• Selection of donor-restricted T cells was primarily mediated by bone marrow-derived cells in the thymus.
• Mixed chimeras showed impaired control of chronic LCMV clone 13 infection.
• Pre-existing memory T cell populations were largely unaffected and maintained ability to control viral rechallenge.

Conclusions:

• Mixed allogeneic chimeras preserve T cell memory and immunocompetence against acute viral infections.
• MHC class I and/or class II matching may be necessary to fully restore immunocompetence against chronic viral infections.
• Thymic selection by bone marrow-derived cells is crucial for donor-restricted T cell development.