Individuals with impaired perforindependent cytotoxic function (Ctx ؊ ) develop a fatal inflammatory disorder called hemophagocytic lymphohistiocytosis (HLH). It has been hypothesized that immune hyperactivation during HLH is caused by heightened infection, defective apoptosis/responsiveness of Ctx ؊ lymphocytes, or enhanced antigen presentation. Whereas clinical and experimental data suggest that increased T-cell activation drives HLH, potential abnormalities of T-cell activation have not been well characterized in Ctx ؊ hosts. To define such abnormalities and to test these hypotheses, we assessed in vivo T-cell activation kinetics and viral loads after lymphocytic choriomeningitis virus (LCMV) infection of Ctx ؊ mice. We found that increased T-cell activation occurred early during infection of Ctx ؊ mice, while they had viral burdens that were identical to those of WT animals, demonstrating that T-cell hyperactivation was independent of viral load. Furthermore, cell transfer and signaling studies indicated that increased antigenic stimulation, not a cellintrinsic defect of responsiveness, underlay heightened T-cell activation in vivo. Finally, direct measurement of viral antigen presentation demonstrated an increase in Ctx ؊ mice that was proportional to abnormal T-cell activation. We conclude that perforin-dependent cytotoxicity has an immunoregulatory role that is distinguishable from its pathogen clearance function and limits T-cell activation in the physiologic context by suppressing antigen presentation. (Blood. 2011; 118(3):618-626)
IntroductionHemophagocytic lymphohistiocytosis (HLH) is a unique childhood disorder characterized by predisposing deficiencies of cytotoxic function, excessive immune activation, and potentially fatal damage to the bone marrow, liver, or brain. 1,2 Because mutations affecting perforin-dependent cytotoxicity were first found in patients with HLH, 3 a variety of speculations have been put forth regarding how they may lead to disease. Most investigators have hypothesized that cell-intrinsic defects of apoptosis, 4,5 proliferation, 6 or lymphocyte homeostasis 7-9 underlie the fatal inflammation seen in humans or mice with defective perforin-dependent cytotoxicity (Ctx Ϫ ). Implicit in these viewpoints is the assumption that cell death, such as that induced by activation or fratricidal killing, limits T-cell activation (in addition to lymphocyte numbers), although this has never been demonstrated in vivo. In other cases, it has been speculated that persistent or abnormal infections may drive HLH. However, in contrast to individuals with severe combined immune deficiencies, uncontrolled infection is not typically observed to be a cause of mortality in HLH. 8,10 An additional long-standing hypothesis relevant to understanding HLH is that cytotoxic lymphocytes may influence antigen presentation by killing APCs. This hypothesis was first proposed by Zinkernagel et al Ͼ 20 years ago, when they demonstrated that CD8-dependent depletion of APCs after viral infection led to suppression of...
