T-cell development is initiated when CD34+ pluripotent stem cells or their immediate progeny leave the bone marrow to migrate to the thymus. Upon arrival in the thymus the stem cell progeny is not yet committed to the T-cell lineage as it has the capability to develop into T, natural killer (NK) and dendritic cells (DC). Primitive hematopoietic progenitor cells in the human thymus express CD34 and lack CD1a. When these progenitor cells develop into T cells they traverse a number of checkpoints. One early checkpoint is the induction of T-cell commitment, which correlates with appearance of CD1a and involves the loss of capacity to develop into NK cells and DC and the initiation of T-cell receptor (TCR) gene rearrangements. Basic helix-loop-helix transcription factors play a role in induction of T-cell commitment. CD1a+CD34+ cells develop into CD4+CD8 alpha+ beta+ cells by upregulating first CD4, followed by CD8 alpha and then CD8 beta. Selection for productive TCR beta gene rearrangements (beta selection) likely occurs in the CD4+CD8 alpha+ beta- and CD4+CD8 alpha+ beta+ populations. Although the T and NK-cell lineages are closely related to each other, NK cells can develop independently of the thymus. The fetal thymus is most likely one site of NK-cell development.

Recently we reported that the human thymus contains a minute population of CD34+CD38dim cells that do not express the T-cell lineage markers CD2 and CD5. The phenotype of this population resembled that of CD34+CD38dim cells present in fetal liver, umbilical cord blood, and bone marrow known to be highly enriched for pluripotent hematopoietic stem cells. In this report we tested the hypothesis that the CD34+CD38dim thymocytes constitute the most primitive hematopoietic cells in the thymus using a combination of phenotypic and functional analyses. It was found that in contrast to CD34+CD38dim cells from fetal liver and bone marrow, CD34+CD38dim cells from the thymus express high levels of CD45RA and are negative for Thy-1. These data indicate that the CD34+CD38dim thymocytes are distinct from pluripotent stem cells. CD34+CD38dim thymocytes differentiate into T cells when cocultured with mouse fetal thymic organs. In addition, individual cells in this population can differentiate either to natural killer cells in the presence of stem cell factor (SCF), interleukin-7 (IL-7), and IL-2 or to dendritic cells in the presence of SCF, granulocyte- macrophage colony-stimulating factor, and tumor necrosis factor alpha(TNFalpha), indicating that CD34+CD38dim thymocytes contain multi- potential hematopoietic progenitors. To establish which CD34+ fetal liver subpopulation contains the cells that migrate to the thymus, we investigated the T-cell-developing potential of CD34+CD38dim and CD34+CD38+ fetal liver cells and found that the capacity of CD34+ fetal liver cells to differentiate into T cells is restricted to those cells that are CD38dim. Collectively, these findings indicate that cells from the CD34+CD38dim fetal liver cell population migrate to the thymus before upregulating CD38 and ommitting to the T-cell lineage.

SUMMARY Recent evidence suggests that T cell apoptosis could be involved in the pathogenesis of HIV‐1 infection. As the progression of HIV‐2 associated disease appears to be slower than that of HIV‐1, we investigated whether there were differences in the degree of T cell death and apoptosis in peripheral blood mononuclear cell (PBMC) cultures from patients with HIV‐1 or HIV‐2 infection. PBMC from healthy controls (n = 28) and patients infected with HIV‐1 (n = 26: asymptomatic (ASY)/persistent generalized lymphadenopathy (PGL). w = 16; and AlDS‐related complex (ARC)AIDS n = 10) or HIV‐2 (n = 30: ASY/PGL, n = 16: ARC/ AIDS, n = 14) were cultured in the absence or presence of mitogens (PHA, PWM) or superantigen (SEB). After 48 h, cell death (CD) was assessed by trypan blue exclusion and in some patients programmed cell death (PCD) was quantified in flow cytometry by measuring the percentage of hypodiploid nuclei corresponding to fragmented DNA, after treating the cells with a propidium iodide hypotonic solution. HlV‐1 and HlV‐2 ARC/AIDS patients and ASY/PGL HIV‐1+ patients had significant increases in cell death percentages compared with controls, both in unstimulated and stimulated lymphocyte cultures. However, HIV‐2+ ASY/FGL patients did not exhibit significant increases of cell death in unstimutated cultures. In addition, the comparison between HIV‐l and HIV‐2 infected subjects in similar stages of disease, showed no significant differences in CD in the ARC AIDS patients, although ASY/PGL HIV‐2‐infected subjects had lower levels of CD than the HIV‐1+ ASY/PGL (3.4%± 0.6 s.e.m. versus 6.8%± M s.e.m., P < 0.01). PCD was significantly increased both in ASY/PGL (14.3%± 2.2 s.e.m., n = 8, P< 0.005) and m ARC/AIDS (25.3%± 4.5 s.e.m., n = 9, P < 0.001) HIV‐1+ patients compared with healthy controls (5.8%± l.7 s.e.m., n = 11). This contrasts with HIV‐2 infected subjects where the ASY/PGL patients (10.0%± 2.8 s.e.m., n = 6) did not differ significantly from healthy controls, although ARC/AIDS patients (27.2%± 4.2 s.e.m., n = 9. P < 0.001) had significantly increased levels of PCD. In conclusion, this is the first report describing the occurrence of spontaneous and activation‐induced lymphocyte death by apoptosis in HlV‐2 infected subjects. The lower levels of PCD in ASY/PGL HlV‐2 infected patients compared with HIV‐T patients at a similar stage justify further investigation to define whether these differences have any rote in the putative slower progression of HlV‐2 disease.

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