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

Abstract

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 α-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-γ 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-γ-inducible protein 10 and MIP-1α 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.

Bystander stimulation of activated CD4+ T cells of unrelated specificity following a booster vaccination with tetanus toxoid

“…Conversely, expansions of anti-viral and antibacterial responses were also noted following vaccination with TT [10,11]. Furthermore, infusion of LPS, which mimics bacterial infections, induces indirect activation of T cells in healthy volunteers [12], confirming similar results observed in mouse models [13,14]. In vitro, human CD4 1 memory T cells appear to be preferential targets for bystander activation, generating a distinct gene expression profile and elevating levels of the extrinsic pathway of apoptosis [15].…”

Genomics of injury

“…The Glue Grant datasets include gene expression data from microarrays as well as large-scale proteomics from high throughput mass spectroscopy (6-12) as well as functional assays from multiplexed Fluorescence Activated Cell Sorting (FACS) (13-14). In these datasets, it becomes clear that technologies for genomics are far more advanced than for proteomics with one reason being genomics is a 4-letter alphabet (four different nucleic acids for both RNA and DNA), whereas, proteomics is a 20-letter alphabet (20 different amino acids in human tissues).…”

Cell-specific expression and pathway analyses reveal alterations in trauma-related human T cell and monocyte pathways

“…For the receptor͞ligand expression and functional analysis of the additional 11 severely injured patients and 15 healthy subjects, 30 ml of venous blood was collected, anticoagulated with EDTA, and processed as described above. T cells and monocytes were stained for four-color flow cytometry as previously described (35). Analysis of T cell functional responses to T cell receptor (CD3CD28) stimulation was as described (9).…”