Primary and secondary immunocompetence in mixed allogeneic chimeras.
Targeted disruption of T cell costimulatory pathways, particularly CD28 and CD40, has allowed for the development of minimally myeloablative strategies for the induction of mixed allogeneic chimerism and donor-specific tolerance across full MHC barriers. In this study we analyze in depth the ability of mixed allogeneic chimeras in two strain combinations to mount effective host-restricted and donor-restricted antiviral CD4 and CD8 responses, as well as the impact of development of mixed chimerism on the maintenance of pre-existing memory populations. While antiviral CD8 responses in mixed chimeras following acute viral infection with lymphocytic choriomeningitis virus Armstrong or vaccinia virus are largely host-restricted, donor-restricted CD8 responses as well as host- and donor-restricted CD4 responses are also readily detected, and virus is promptly cleared. We further demonstrate that selection of donor-restricted T cells in mixed chimeras is principally mediated by bone marrow-derived cells in the thymus. Conversely, we find that mixed chimeras exhibit a deficit in their ability to deal with a chronic lymphocytic choriomeningitis virus clone 13 infection. Encouragingly, pre-existing memory populations are largely unaffected by the development of high level mixed chimerism and maintain the ability to control viral rechallenge. Our results suggest that while pre-existing T cell memory and primary immunocompetence to acute infection are preserved in mixed allogeneic chimeras, MHC class I and/or class II tissue matching may be required to fully preserve immunocompetence in dealing with chronic viral infections.
Williams
Matthew A
MA
Emory Transplant Center and Department of Surgery, Emory University School of Medicine, Atlanta, GA, 30322, USA.
Adams
Andrew B
AB
Walsh
Melody B
MB
Shirasugi
Nozomu
N
Onami
Thandi M
TM
Pearson
Thomas C
TC
Ahmed
Rafi
R
Larsen
Christian P
CP
D000818:Animals; D001117:Arenaviridae Infections / Q000235:genetics / Q000276:immunology / Q000821:virology; D016026:Bone Marrow Transplantation / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D006410:Hematopoiesis / Q000235:genetics / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007117:Immunization, Secondary; D007121:Immunocompetence / Q000235:genetics* / Q000276:immunology; D007156:Immunologic Memory / Q000235:genetics; D007519:Isoantigens / Q000235:genetics* / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011828:Radiation Chimera / Q000276:immunology*; D013045:Species Specificity; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000821:virology; D014407:Tumor Cells, Cultured; D014615:Vaccinia / Q000235:genetics / Q000276:immunology / Q000821:virology; D014616:Vaccinia virus / Q000276:immunology
D007519:Isoantigens