PubMed · 11366937
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P Simmons. 1999. Pathogenesis puzzle.. https://pubmed.ncbi.nlm.nih.gov/11366937/
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Recent advances in class II tetramer staining technology have allowed reliable direct ex vivo visualization of antigen-specific CD4 T cells. In order to define the frequency and phenotype of a prototype response to a nonpersistent pathogen, we have used such techniques to analyze influenza virus-specific memory CD4 T cells directly from blood. These responses are stably detectable ex vivo at low frequencies (range, 0.00012 to 0.0061% of CD4 T cells) and display a distinct "central memory" CD62L(+) phenotype.
In normal human subjects a small proportion of peripheral blood T-cells simultaneously express both CD4 and CD8 differentiation antigens. In this study we characterized a subset of CD4+ clones, from a healthy donor, that is specific for the thyrotropin receptor (TSHR) and that showed cells co-expressing the CD8 receptor. To address whether the expression of the CD8 receptor on the cell membrane was associated to differences in the physiology of the T-cells, we isolated, from the same clone, CD4 single positive (SP) cells from those co-expressing CD4/CD8 receptors (DP cells) and stimulated them in vitro with antigen presenting cells (APC) carrying TSHR. The results demonstrated that CD8 co-expression has a profound effect on the physiology of T helper (Th) cells. In comparison to cells expressing the CD4 receptor alone, DP T-cells showed: (1) increased proliferation; (2) higher and more sustained release of free Ca2+ in the cytosol, under stimulus; (3) lower levels of IL-2 and IL-4 released in the supernatants; (4) increased amounts of IFN-gamma released.
The expression profiles of eight cell lines derived from T-cell malignancies were compared to CD4-positive T-cells using cDNA microarray technology. Unsupervised hierarchical clustering of 4364 genes demonstrated substantial heterogeneity resulting in four distinct groups. While no genes were found to be uniformly up- or down-regulated across all cell lines, we observed 111 over-expressed genes (greater than two-fold) and 1118 down-regulated genes (greater than two-fold) in the lymphomas as a group when compared to CD4-positive T-cells. These included genes involved in cytokine signaling, cell adhesion, cytoskeletal elements, nuclear transcription factors, and known oncogenes and tumor suppressor genes. Quantitative fluorescent reverse transcription-polymerase chain reaction analysis demonstrated 70% concordance with the microarray results. While freshly isolated malignant cells may differ in their individual expression patterns relative to established cell lines from the same diagnoses, we feel that the variety of different lymphocytic cell lines that we examined provides a representative picture of the molecular pathogenesis of T-cell malignancies.