The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20062602
The Journal of Experimental Medicine, Vol. 204, No. 6, 1463-1474
The Rockefeller University Press, 0022-1007 $30.00
© Delano et al.
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ARTICLE

 MyD88-dependent expansion of an immature GR-1+CD11b+ population induces T cell suppression and Th2 polarization in sepsis

Matthew J. Delano1, Philip O. Scumpia1, Jason S. Weinstein2, Dominique Coco2, Srinivas Nagaraj4, Kindra M. Kelly-Scumpia2, Kerri A. O'Malley1, James L. Wynn1, Svetlana Antonenko5, Samer Z. Al-Quran2, Ryan Swan6, Chun-Shiang Chung6, Mark A. Atkinson2, Reuben Ramphal3, Dmitry I. Gabrilovich4, Wesley H. Reeves2, Alfred Ayala6, Joseph Phillips5, Drake LaFace5, Paul G. Heyworth5, Michael Clare-Salzler2, and Lyle L. Moldawer1

1 Department of Surgery, 2 Department of Pathology, Immunology and Laboratory Medicine, and 3 Department of Medicine, University of Florida College of Medicine, Gainesville, FL 32610
4 Department of Cancer Biology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL 33612
5 Schering-Plough Biopharma, Palo Alto, CA 94304
6 Department of Surgery, Rhode Island Hospital and Brown University School of Medicine, Providence, RI 02903

CORRESPONDENCE Lyle L. Moldawer: moldawer{at}surgery.ufl.edu

Polymicrobial sepsis alters the adaptive immune response and induces T cell suppression and Th2 immune polarization. We identify a GR-1+CD11b+ population whose numbers dramatically increase and remain elevated in the spleen, lymph nodes, and bone marrow during polymicrobial sepsis. Phenotypically, these cells are heterogeneous, immature, predominantly myeloid progenitors that express interleukin 10 and several other cytokines and chemokines. Splenic GR-1+ cells effectively suppress antigen-specific CD8+ T cell interferon (IFN) {gamma} production but only modestly suppress antigen-specific and nonspecific CD4+ T cell proliferation. GR-1+ cell depletion in vivo prevents both the sepsis-induced augmentation of Th2 cell–dependent and depression of Th1 cell–dependent antibody production. Signaling through MyD88, but not Toll-like receptor 4, TIR domain–containing adaptor-inducing IFN-ß, or the IFN-{alpha}/ß receptor, is required for complete GR-1+CD11b+ expansion. GR-1+CD11b+ cells contribute to sepsis-induced T cell suppression and preferential Th2 polarization.

Abbreviations used: APC, allophycocyanin; MIP, macrophage inflammatory protein; NP-KLH, 4-hydroxy-3-nitrophenyl acetyl–KLH; RANTES, regulated on activation, normall T cell expressed and secreted; TLR, Toll-like receptor; TRIF, TIR domain–containing adaptor-inducing IFN-ß.


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