Sepsis-Induced Apoptosis Leads to Active Suppression of Delayed-Type Hypersensitivity by CD8+ Regulatory T Cells through a TRAIL-Dependent Mechanism

Abstract

Patients who survive severe sepsis often display severely compromised immune function. One hallmark of such immune suppression in septic patients is an impaired delayed-type hypersensitivity (DTH) response, manifested by a loss of skin testing to recall Ags. Because sepsis induces significant apoptosis in lymphoid and myeloid cells, and apoptotic cells are themselves tolerogenic, we tested the hypothesis that suppression of DTH is mediated by tolerogenic properties of the apoptotic cells generated during sepsis. Mice subjected to cecal ligation and puncture demonstrated a loss of DTH for the 7 d following cecal ligation and puncture; however, the immune response returned to normal by day 10. Blocking sepsis-induced apoptosis via Bcl-2 overexpression or Bim deficiency prevented the loss of DTH. Importantly, injection of apoptotic cells into Bim−/− mice prevented an effective DTH response, thereby suggesting a causal link between apoptotic cells and immune suppression. Surprisingly, when TRAIL null mice were examined, we found that these animals had significant apoptosis but retained their DTH responses. Further studies revealed that apoptotic cells generated during sepsis induced a CD8+ regulatory T cell that suppressed DTH by TRAIL production. These results establish a link between apoptotic cells and immune suppression during sepsis and suggest TRAIL may be a viable therapeutic target for boosting the adaptive immune response following sepsis.

Balanced control of both hyper and hypo-inflammatory phases as a new treatment paradigm in sepsis

“…Additional evidence for the sepsis-associated immunosuppression is the high incidence of herpes virus reactivation that occurs in patients with prolonged septic episodes (5). These clinical observations are supported from in vitro data showing impaired cytotoxicity and increased apoptosis of immune effectors from septic patients (6).…”

An Immunogenic Peptide in the A-box of HMGB1 Protein Reverses Apoptosis-induced Tolerance through RAGE Receptor

“…It is now well established that following an early cytokine storm, sepsis patients become severely immunosuppressed, which renders them susceptible to secondary nosocomial infections. Human and animal studies indicate that massive leukocyte apoptosis occurs in sepsis and suppresses immunity by triggering a tolerogenic program in antigen-presenting cells (2)(3)(4)(5)(6)(7)(8)(9)(10). As a result, sepsis patients have impaired delayed-type hypersensitivity (DTH) 7 and are often unable to mount an immune response to recall antigens (11,12).…”

Distinct pathophysiologic mechanisms of septic acute kidney injury

“…Sepsis has traditionally been considered an excessive systemic inflammatory response to invading pathogens; however, several clinical trials have shown that suppression of inflammation has no effect on sepsis-induced AKI (6,7). Previous study demonstrated the occurrence of compensated anti-inflammatory response syndrome follows systemic inflammatory response syndrome (8), and according to recent observations, mortality from sepsis or sepsis-induced organ dysfunction might be associated with paradoxical immune suppression, characterized by unregulated apoptosis of immune cells (9)(10)(11)(12).…”