Monday, November 20, 2006

TRAIL-R attenuates innate immunity

drj writes: "TRAIL, officially known as TNFSF10, induces apoptosis of virus-infected or transformed cells but not normal cells, suggesting a potentially "magic bullet" therapeutic. TRAIL expression is inducible on immune effector cells: Natural Killers (NK) and T cells, macrophages, and dendritic cells. TRAIL knockout mice are more susceptible to tumor metastasis and chemical carcinogenesis. TRAIL-R (receptor) expression is apparently induced by transformation or infection.
Here, Diehl and collegues describe the generation and characterization of TRAIL-R knockout (TRAIL-R-KO) mice. (Mice have only one signaling receptor; humans have two: TNFRSF10A, B.) TRAIL-R-KO mice have normal lymphocyte populations but produce more of the cytokines IL-12, IFN-alpha, and IFN-gamma and clear cytomegalovirus more rapidly. TRAIL-R-KO macrophages stimulated with pathogen-derived molecules (e.g., LPS) though the Toll-like receptors show increased TRAIL expression and enhanced cytokine production. Although early signaling is normal, activation of the transciption factor NF-kB and degradation of its inhibitor IkB-a is prolonged (12 h).
What is the point of inhibiting the innate response? Unlike the adaptive response, there are no expanded populations of cells to inactivate and remove." PubMed Diehl et al., Immunity 21:877-889, December, 2004
TRAIL-R as a Negative Regulator of Innate Immune Cell Responses


Anonymous said...

other inhibitors? consequences?

Are there other suppressive pathways for the pathogens whose innate responses are not suppressed by TRAIL-R? Or does the TRAIL-R suppression of the innate response contribute to the chronic infection by murine CMV [] ? The details of how the infected mice "clear" cytomegalovirus could be interesting but are not provided in this paper.

Anonymous said...

Re:other inhibitors? consequences?

Cytomegaloviruses are not cleared but persist throughout life in the infected host. They are able to escape the immune response by inhibiting the presentation of viral peptides [] to CD8+ T cells.

Reuel said...

Re:other inhibitors? consequences?

The details of how the murine immune system clears MCMV have been described extensively (see, e.g. Christine Biron's lab). The point of this study is to demonstrate that one well characterized mechanisms for MCMV clearance (enhanced cytokine responses) is regulated by TRAIL-R, while another mechanism, NK cell cytolytic activity, is not.

It is possible that TRAIL-R has some roles in chronic infection; however, the study implicates TRAIL-R primarily in the acute-phase early response, and there have been no reliable reports of TRAIL-R function in T-cell memory responses.