NDLI: Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling

Content Provider	PubMed Central
Author	Paulos, Chrystal M. Wrzesinski, Claudia Kaiser, Andrew Hinrichs, Christian S. Chieppa, Marcello Cassard, Lydie Palmer, Douglas C. Boni, Andrea Pawel, Muranski Yu, Zhiya Luca, Gattinoni Antony, Paul A. Rosenberg, Steven A. Restifo, Nicholas P.
Copyright Year	2007
Abstract	Lymphodepletion with total body irradiation (TBI) increases the efficacy of adoptively transferred tumor-specific CD8+ T cells by depleting inhibitory lymphocytes and increasing homeostatic cytokine levels. We found that TBI augmented the function of adoptively transferred CD8+ T cells in mice genetically deficient in all lymphocytes, indicating the existence of another TBI mechanism of action. Additional investigation revealed commensal gut microflora in the mesenteric lymph nodes and elevated LPS levels in the sera of irradiated mice. These findings correlated with increased dendritic cell activation and heightened levels of systemic inflammatory cytokines. Reduction of host microflora using antibiotics, neutralization of serum LPS using polymyxin B, or removal of LPS signaling components using mice genetically deficient in CD14 and TLR4 reduced the beneficial effects of TBI on tumor regression. Conversely, administration of microbial ligand–containing serum or ultrapure LPS from irradiated animals to nonirradiated antibody-lymphodepleted mice enhanced CD8+ T cell activation and improved tumor regression. Administration of ultrapure LPS to irradiated animals further enhanced the number and function of the adoptively transferred cells, leading to long-term cure of mice with large B16F10 tumors and enhanced autoimmune vitiligo. Thus, disruption of the homeostatic balance between the host and microbes can enhance cell-based tumor immunotherapy.
Related Links	http://dx.doi.org/10.1172/jci32205
Ending Page	2204
Page Count	8
Starting Page	2197
File Format	PDF
ISSN	00219738
Journal	Journal of Clinical Investigation
Issue Number	8
Volume Number	117
Language	English
Publisher	American Society for Clinical Investigation
Publisher Date	2007-08-01
Access Restriction	Open
Rights Holder	American Society for Clinical Investigation
Subject Keyword	Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Medicine

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