Perforin is a critical physiologic regulator of T-cell activation

• Published in: Blood Vol. 118; no. 3; pp. 618 - 626
• Main Authors: Lykens, Jennifer E., Terrell, Catherine E., Zoller, Erin E., Risma, Kimberly, Jordan, Michael B.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 21.07.2011; Americain Society of Hematology; American Society of Hematology
• Subjects: Animals; Antigen Presentation - immunology; Antigens, Viral - immunology; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - virology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - virology; Cell Communication - immunology; Hematologic and hematopoietic diseases; Immunobiology; Lymphocyte Activation - physiology; Lymphocytic Choriomeningitis - immunology; Lymphocytic choriomeningitis virus; Lymphohistiocytosis, Hemophagocytic - immunology; Lymphohistiocytosis, Hemophagocytic - physiopathology; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Perforin; Pore Forming Cytotoxic Proteins - genetics; Pore Forming Cytotoxic Proteins - immunology; Regulator; Cytolysin; Hematology; Perforin; T-Lymphocyte
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2010-12-324533

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.