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Selective Activation of Peripheral Blood T Cell Subsets by Endotoxin Infusion in Healthy Human Subjects Corresponds to Differential Chemokine Activation¹

Asit K. De^2,*, Carol L. Miller-Graziano^2,3,*, Steve E. Calvano, Krzysztof Laudanski^*, Stephen F. Lowry, Lyle L. Moldawer, Daniel G. Remick, Jr, Natasa Rajicic^¶, David Schoenfeld^¶ and Ronald G. Tompkins^¶

^* Department of Surgery, University of Rochester Medical Center, Rochester, NY 14627; Department of Surgery, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ 08854; Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610; Department of Medical Science, University of Michigan, Ann Arbor, MI 48109; and ^¶ Department of Surgery and MGH Biostatistics, Massachusetts General Hospital and the Shriners Burn Hospital, Harvard Medical School, Boston, MA 02114

Although activation of human innate immunity after endotoxin administration is well established, in vivo endotoxin effects on human T cell responses are not well understood. Most naive human T cells do not express receptors for LPS, but can respond to endotoxin-induced mediators such as chemokines. In this study, we characterized the in vivo response of peripheral human T cell subsets to endotoxin infusion by assessing alterations in isolated T cells expressing different phenotypes, intracellular cytokines, and systemic chemokines concentration, which may influence these indirect T cell responses. Endotoxin administration to healthy subjects produced T cell activation as confirmed by a 20% increase in intracellular IL-2, as well as increased CD28 and IL-2R -chain (CD25) expression. Endotoxin induced indirect activation of T cells was highly selective among the T cell subpopulations. Increased IL-2 production (36.0 ± 3.7 to 53.2 ± 4.1) vs decreased IFN- production (33.8 ± 4.2 to 19.1 ± 3.2) indicated selective Th1 activation. Th2 produced IL-13 was minimally increased. Differentially altered chemokine receptor expression also indicated selective T cell subset activation and migration. CXCR3⁺ and CCR5⁺ expressing Th1 cells were decreased (CXCR3 44.6 ± 3.2 to 33.3 ± 4.6 and CCR5 24.8 ± 2.3 to 12 ± 1.4), whereas plasma levels of their chemokine ligands IFN--inducible protein 10 and MIP-1 were increased (61.4 ± 13.9 to 1103.7 ± 274.5 and 22.8 ± 6.2 to 55.7 ± 9.5, respectively). In contrast, CCR4⁺ and CCR3 (Th2) proportions increased or remained unchanged whereas their ligands, eotaxin and the thymus and activation-regulated chemokine TARC, were unchanged. The data indicate selective activation among Th1 subpopulations, as well as differential Th1/Th2 activation, which is consistent with a selective induction of Th1 and Th2 chemokine ligands.

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				K. Laudanski, C. Miller-Graziano, W. Xiao, M. N. Mindrinos, D. R. Richards, A. De, L. L. Moldawer, R. V. Maier, P. Bankey, H. V. Baker, et al. Cell-specific expression and pathway analyses reveal alterations in trauma-related human T cell and monocyte pathways PNAS, October 17, 2006; 103(42): 15564 - 15569. [Abstract] [Full Text] [PDF]