Relationships between T lymphocyte apoptosis and anergy following trauma

Severely injured trauma patients experience T cell depletion. A subset of these patients also develop T cell unresponsiveness (anergy), as characterized by the failure of their T cells to proliferate or to produce T lymphokines in response to a direct stimulus through the T cell receptor. We hypothesized that T cell apoptosis plays a role in the development of posttrauma T cell depletion and/or T cell anergy by deleting an activated T cell population. We found that moderately increased T cell depletion posttrauma is not innately deleterious or immediately responsible for anergy, but may predispose to later development of T cell anergy, possibly due to a more stringent requirement for activation of the remaining naive T cells.

A total of 30 blunt trauma and burn patients were assessed twice weekly for the following parameters: (1) clinical outcome expressed as severity of organ dysfunction as measured by the multiple organ dysfunction syndrome score, (2) proliferative response of highly purified T cells to anti-CD3/anti-CD4, (3) level of apoptosis as determined by flow cytometric analysis of propidium iodide-stained monocyte reduced peripheral blood mononuclear cells, either unstimulated or in response to mitogenic challenge or Fas (CD95) stimulation.

A wide range of apoptosis levels are seen in the patients' T cells. Apoptosis is increased when all trauma patients' T cells are compared to T cells of normal volunteers. However, at the time a patients' T cells are anergic, there is no increased level of apoptosis. In fact, the point of maximum anergy (lowest proliferative response) correlates to diminished apoptotic response. Increased T cell apoptosis can be stimulated by anti-Fas antibody in trauma patients' responsive T cells but not in maximally anergic T cells. These data suggest that patients' T cell anergy is not an immediate result of apoptotic T cell depletion upon stimulation. However, patients who later develop T cell anergy have increased T cell apoptosis earlier in their clinical course than patients who never experience T cell anergy.

Increased levels of apoptosis are not directly associated with negative trauma patient outcome nor the immediate cause of T cell anergy. However, unusually high levels of apoptosis and development of severe T cell depletion occurring before complete activation and expansion of the posttrauma T cell response may presage anergy and subsequent organ failure.