TNF regulates thymocyte production by apoptosis and proliferation of the triple negative (CD3-CD4-CD8-) subset.

TNF is a proinflammatory cytokine with opposing death/no-death effects in vivo and in vitro. Our studies showed that TNF regulates mouse thymocyte production, inducing both apoptosis and proliferation of the most immature CD3(-)CD4(-)CD8(-) triple negative (TN) subset within a broad range of dosages (10(1)-10(5) pg/ml) in the presence of IL-7. TNF apoptosis affected only the TN3 (CD44(-)CD25(+)) and TN4 (CD44(-)CD25(-)) subsets that expressed both TNFR-p55 and -p75.

[Immunology of the future].

Immunology is a young science, much younger than MEDICINA, since its modern biological foundations were established only in the 70s-80s with the definition of the T and B cell receptors. In spite of its relative youth, many key basic biological knowledge such as signal transduction, gene recombination, apoptosis and cell cycle regulation have been initiated or expanded using cells from the immune system. Although it is not easy to predict the future, we include in this essay eight areas in which we can expect important developments.

Cell cycle-dependent tumor necrosis factor apoptosis.

To determine if tumor necrosis factor (TNF)-mediated apoptosis affects cells at defined stages of the cell cycle, WEHI-164/2F (WEHI) cells were synchronized at G0-G1 after 3-day cultures in medium containing RPMI 1640 and 0.5% FCS (RPMI-0.5% FCS).

Uncoupling IL-2 production from apoptosis and TNF production by changing the signal through the TCR.

T cells may discriminate between stimuli in a variety of ways, including the presence of cytokines or other costimulatory signals, the type of Ag (peptide, superantigen, or allorecognition), or the magnitude of the signal through the TCR. We have used anti-CD3 stimulation of T hybridomas to examine signals generated through the TCR in the absence of exogenous APCs. Soluble whole anti-CD3, but not F(ab')2 anti-CD3, was able to stimulate the T hybridomas to produce IL-2.

Immune functions of tumor necrosis factor. I. Tumor necrosis factor induces apoptosis of mouse thymocytes and can also stimulate or inhibit IL-6-induced proliferation depending on the concentration of mitogenic costimulation.

Murine rTNF produces at least three effects on mouse thymocytes in vitro: 1) Is a modest co-stimulator of proliferation with low PHA-P doses. 2) Has a bi-directional interaction with rIL-6-depending on PHA concentration: at low PHA (5 to 10 micrograms/ml) TNF augments and at high PHA (20 to 30 micrograms/ml) inhibits IL-6-induced proliferation. A comparable bidirectional PHA dose-dependent TNF interaction was seen with IL-1 beta, whereas only inhibition at high PHA with IL-2 and only augmentation at low PHA with IL-4 were seen.