Perforin is a critical physiologic regulator of T-cell activation

JE Lykens, CE Terrell, EE Zoller… - Blood, The Journal …, 2011 - ashpublications.org
JE Lykens, CE Terrell, EE Zoller, K Risma, MB Jordan
Blood, The Journal of the American Society of Hematology, 2011ashpublications.org
Individuals with impaired perforin-dependent 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 …
Abstract
Individuals with impaired perforin-dependent 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 cell-intrinsic 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.
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