| First Author | Terrell CE | Year | 2013 |
| Journal | Blood | Volume | 121 |
| Issue | 26 | Pages | 5184-91 |
| PubMed ID | 23660960 | Mgi Jnum | J:200959 |
| Mgi Id | MGI:5510310 | Doi | 10.1182/blood-2013-04-495309 |
| Citation | Terrell CE, et al. (2013) Perforin deficiency impairs a critical immunoregulatory loop involving murine CD8(+) T cells and dendritic cells. Blood 121(26):5184-91 |
| abstractText | Humans and mice with impaired perforin-dependent cytotoxic function may develop excessive T-cell activation and the fatal disorder hemophagocytic lymphohistiocytosis (HLH) after infection. Though cytotoxic lymphocytes can kill antigen-presenting cells, the physiological mechanism of perforin-mediated immune regulation has never been demonstrated in a disease-relevant context. We used a murine model of HLH to examine how perforin controls immune activation, and we have defined a feedback loop that is critical for immune homeostasis. This endogenous feedback loop involves perforin-dependent elimination of rare, antigen-presenting dendritic cells (DCs) by CD8(+) T cells and has a dominant influence on the magnitude of T-cell activation after viral infection. Antigen presentation by a minor fraction of DCs persisted in T-cell- or perforin-deficient animals and continued to drive T-cell activation well beyond initial priming in the latter animals. Depletion of DCs or transfer of perforin-sufficient T cells dampened endogenous DC antigen presentation and T-cell activation, demonstrating a reciprocal relationship between perforin in CD8(+) T cells and DC function. Thus, selective cytotoxic "pruning" of DC populations by CD8(+) T cells limits T-cell activation and protects against the development of HLH and potentially other immunopathological conditions. |
