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

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 (cid:1) -chain (CD25) expression. Endotoxin induced indirect activation of T cells was highly selective among the T cell subpopulations. Increased IL-2 production (36.0 (cid:2) 3.7 to 53.2 (cid:2) 4.1) vs decreased IFN- (cid:3) production (33.8 (cid:2) 4.2 to 19.1 (cid:2) 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 (cid:4) and CCR5 (cid:4) expressing Th1 cells were decreased (CXCR3 44.6 (cid:2) 3.2 to 33.3 (cid:2) 4.6 and CCR5 24.8 (cid:2) 2.3 to 12 (cid:2) 1.4), whereas plasma levels of their chemokine ligands IFN- (cid:3) -inducible protein 10 and MIP-1 (cid:1) were increased (61.4 (cid:2) 13.9 to 1103.7 (cid:2) 274.5 and 22.8 (cid:2) 6.2 to 55.7 (cid:2) 9.5, respectively). In contrast, CCR4 (cid:4) 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. The Journal of Immunology, 2005, 175: 6155–6162. were increased or unchanged. These T cell subpopulation alterations parallel a plasma increase in the CXCR3 ligand, IP-10, the CCR2 ligand, MCP-1, and the CCR5 ligand, MIP-1 (cid:2) . In striking contrast, the CCR3 ligand, eotaxin, and the CCR4 ligand, thymus and activation-regulated chemokine (TARC), were unaltered. Selective T cell emigration, in response to endotoxin infusion, was further suggested by an increasing numbers of CCR7-expressing central memory T cells in the face of generalized circulating T cell reduction. Thus, these data indicate a novel selective split activation of the human Th1 subsets in addition to differential Th1 vs Th2 activation as an indirect response to endotoxin-induced innate immunity and may reflect the novel differential chemokine activation also detected after endotoxin infusion.

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