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Lymphopenia-Induced Homeostatic Proliferation of CD8⁺ T Cells Is a Mechanism for Effective Allogeneic Skin Graft Rejection following Burn Injury¹

Robert Maile^*,, Carie M. Barnes^*, Alma I. Nielsen^*, Anthony A. Meyer^*, Jeffrey A. Frelinger and Bruce A. Cairns^2,*,

^* Department of Surgery and Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599

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.

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