Lymphopenia-induced homeostatic proliferation of CD8+ T cells is a mechanism for effective allogeneic skin graft rejection following burn injury.
Burn patients are immunocompromised yet paradoxically are able to effectively reject allogeneic skin grafts. Failure to close a massive burn wound leads to sepsis and multiple system organ failure. Immune suppression early (3 days) after burn injury is associated with glucocorticoid-mediated T cell apoptosis and anti-inflammatory cytokine responses. Using a mouse model of burn injury, we show CD8+ T cell hyperresponsiveness late (14 days) after burn injury. This is associated with a CD8+ T cell pro- and anti-inflammatory cytokine secretion profile, peripheral lymphopenia, and accumulation of a rapidly cycling, hyperresponsive memory-like CD8+CD44+ IL-7R- T cells which do not require costimulation for effective Ag response. Adoptive transfer of allospecific CD8+ T cells purified 14 days postburn results in enhanced allogeneic skin graft rejection in unburned recipient mice. Chemical blockade of glucocorticoid-induced lymphocyte apoptosis early after burn injury abolishes both the late homeostatic accumulation of CD8+ memory-like T cells and the associated enhanced proinflammatory CD8+ T cell response, but not the late enhanced CD8+ anti-inflammatory response. These data suggest a mechanism for the dynamic CD8+ T cell response following injury involving an interaction between activation, apoptosis, and cellular regeneration with broad clinical implications for allogeneic skin grafting and sepsis.
Maile
Robert
R
Department of Surgery, University of North Carolina, Chapel Hill, NC 27599, USA.
Barnes
Carie M
CM
Nielsen
Alma I
AI
Meyer
Anthony A
AA
Frelinger
Jeffrey A
JA
Cairns
Bruce A
BA
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002056:Burns / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology* / Q000637:transplantation; D002453:Cell Cycle / Q000276:immunology; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006131:Growth Inhibitors / Q000008:administration & dosage; D006706:Homeostasis / Q000276:immunology*; D007156:Immunologic Memory; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015735:Mifepristone / Q000008:administration & dosage; D016038:Skin Transplantation / Q000276:immunology* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D013997:Time Factors
D016207:Cytokines; D006131:Growth Inhibitors; D015735:Mifepristone