Interleukin 4 is a growth factor for activated thymocytes: possible role in T-cell ontogeny.

Abstract

We have shown that recombinant or natural interleukin 4 (IL-4) (formerly called B-cell stimulatory factor 1) induces proliferation of activated adult or fetal thymocytes. In the case of adult thymocytes, IL-4 in combination with Con A or phorbol 12-myristate 13-acetate (PMA) stimulated the proliferation of peanut agglutinin (PNA)-negative (-) thymocytes, while PNA-positive (+) thymocytes showed only marginal responses. Further investigation revealed that day 14-17 fetal thymocytes, purified L3T4-LyT2-double-negative adult thymocytes, and single positive L3T4+ LyT2-or L3T4-LyT2+ thymocytes failed to respond to IL-4 or PMA alone but proliferated strongly with both IL-4 and PMA. In contrast, purified double-positive L3T4+ LyT2+ adult thymocytes showed only a marginal proliferative response to these stimuli. Responsiveness of thymic subpopulations to PMA and IL-4 could be inhibited with anti-IL-4 but not with anti-IL-2 monoclonal antibodies, indicating that they were IL-2 independent. Finally, we have observed that supernatants from calcium ionophore and PMA-stimulated adult double-negative L3T4-LyT2-thymocytes induce proliferation of doublenegative adult thymocytes. This latter response is inhibited by anti-IL-4 monoclonal antibodies, suggesting that under appropriate stimulation conditions, these immature thymocytes are able to produce IL-4. These observations suggest a role for IL-4 in T-cell ontogeny.

A Role for Tumor Necrosis Factor-α and Interferon-γ in the Regulation of Interleukin-4-Induced Human Thymocyte Proliferation In Vitro. Heightened Sensitivity in the Down Syndrome (Trisomy 21) Thymus

“…Human TCRy,G cells are CD3+ and predominantly CD4-CD8-(41-43), although expression of CD4 (43, 5 1) and CD8 (41-43) on TCRy,G cells has been observed. Our demonstration that human TCRy,G-bearing thymocytes proliferate in response to IL-4 is consistent with reports in the murine system that IG4-responsive thymocytes are generally CD4-CD8-(1 5,16,19,21,27). It is also consistent with reports suggesting that IL-4-responsive human thymocytes (24) or bone marrow cells (52) are CD3+.…”

“…8, legend), this is unlikely to explain the increased sensitivity to IFN-y or TNF, because there was no correlation between responsiveness to inhibition by IFN-y or TNF and the level of IL-4-induced proliferation of a given thymocyte preparation. DISCUSSION We have demonstrated that postnatal human thymocytes from both control and DS children proliferate in a dose-dependent manner to IL-4 and that this proliferation is unlike the IL-4-mediated proliferation of murine thymocytes, which requires a second signal such as that supplied by mitogen or phorbol ester (15)(16)(17)(18)(19)(20)(21). This difference between the response of human and murine thymocytes may be explained by differences in either the number or affinity of IG4 receptors on thymocytes.…”

“…There is also evidence that IL-4 is a differentiation factor for immature T cell precursors in fetal murine (15) or postnatal human thymus (25,26). Support for an important role of IL-4 in thymocyte proliferation and differentiation is strengthened by the observations that immature murine thymocytes express high affinity receptors for IL-4 (27) and can be stimulated to produce IL-4 in vitro (16,28,29). In addition, constitutive expression of IL-4 mRNA has been identified by in situ hybridization in fetal murine thymocytes (30) and in CD3-CD4-CD8-T cell precursors isolated from postnatal human thymus (26).…”

Immunocytochemical demonstration of the binding and internalization of growth hormone, B-cell stimulating factor-1 and thy-1.2 in murine lymphocytes.

“…ascites cells (28). In the immune system, proliferation and differentiation of activated B-cells into memory cells or plasma cells to produce antibody was modulated by the polypeptides called B-cell stimulating factors (BSFs) secreted by T-cells (19,30). Using radiolabelled T cell growth factor (TCGF), Robb et al (24) have demonstrated that TCGF interacts with T cells through a specific receptor similar to the reactions of polypeptide hormones.…”

“…BCGF-1 has also been known as BSF-1 (22) or interleukin-4 (IL-4) (17,30). BSF-1/IL-4 is a glycoprotein with a molecular weight of 20,000 Daltons (18).…”