Selective up‐regulation by interferon‐γ of surface molecules of the Ly‐6 complex in resting T cells: the Ly‐6A/E and TAP antigens are preferentially enhanced

Abstract

Surface molecules encoded by the murine Ly-6 locus can transduce triggering signals in T cells and thus may play important roles in T cell function. Previously, we found that Ly-6 molecules are up-regulated by interferon (IFN)-alpha/beta in resting T cells. Here, we examined the possible influence of IFN-gamma on these molecules. Purified T cells from C57BL/6 (Ly-6.2) and BALB/c (Ly-6.1) mice were incubated in vitro with recombinant murine IFN-gamma and the expression of Ly-6 antigens was measured by flow cytofluorometry. It was found that both Ly-6A/E and T cell-activating protein (TAP) molecules are markedly enhanced while Ly-6C is less affected. Under the same conditions, other T cell surface molecules showed no or marginal changes. The effect of IFN-gamma on Ly-6A/E and TAP expression reached a maximum with as little as 10 U/ml and required only 18-24 h of incubation. Moreover, the enhancement of Ly-6A expression induced by IFN-gamma was stable for at least 5 days. Analysis of T cell subsets further revealed that IFN-gamma-induced augmentation of Ly-6A (C57BL/6 mice) involves both Lyt-2+ and L3T4+ cells while the increase of Ly-6E (BALB/c mice) is more pronounced in Lyt-2+ cells. The functional consequence of these phenotypic alterations was evaluated by studying the mitogenic responses of T cells to antibody-mediated Ly-6 cross-linking in the presence of phorbol myristate acetate. Pretreatment of resting T cells with IFN-gamma dramatically increased the responses to anti-Ly-6A and anti-Ly-6E monoclonal antibodies. IFN-gamma treatment also boosted the stimulation induced by anti-TAP monoclonal antibody when this stimulation was performed under suboptimal conditions. Therefore, IFN-gamma selectively up-regulates the Ly-6A/E and TAP activation pathways in resting T cells. We speculate that this effect may contribute to the immunoregulatory activities of IFN-gamma.

Hematopoietic stem cell and progenitor defects in Sca-1/Ly-6A–null mice

“…The simplest explanation for the dramatic reduction in Sca-1 Ϫ/Ϫ HSCrepopulating ability between primary and secondary BM transplantations is that Sca-1 plays an important role in HSC self-renewal, at least in response to hematologic stress caused by lethal irradiation and transplantation. This explanation is consistent with the regulation of Sca-1 by interferons 25,26 and tumor necrosis factor-␣ (TNF-␣), 27 which are known to be induced in response to (1) cellular stress; (2) Under homeostatic conditions (ie, Sca-1-null mice), Sca-1 is not required for stem cell maintenance, which is consistent with a role for Sca-1 as a coregulator of cell signaling; in this case, however, a coregulator of the signals that mediate stem cell self-renewal. A postulated molecular role of Sca-1 and other GPI-anchored proteins is to modulate signaling by Src family kinases, receptor tyrosine kinases, and other signaling molecules in lipid rafts.…”

Constitutive JAK3 activation induces lymphoproliferative syndromes in murine bone marrow transplantation models

“…Of note, JAK3-AV CD8 ϩ T cells also show high Ly6C expression and IFN␥ secretion, both of which have previously been associated with higher proliferative capacities of T cells. 40 Interestingly, IFN␥ itself induces Ly6C up-regulation and selective CD8 ϩ T cells proliferation in vivo, 41,42 suggesting that the T-cell lymphoma induced by constitutive JAK3 activation may in part result from a positive feedback loop involving IFN␥ and Ly-6C, leading to aberrant proliferation of CD8 ϩ T cells. In addition, constitutive JAK3 activation also increases resistance to apoptosis in thymocytes and induces up-regulation of the antiapoptotic effector Bcl-2 in DP, CD4 ϩ SP, and CD8 ϩ SP T cells, suggesting that the observed phenotype also results from enhanced survival of these cells.…”

Kinetic analysis of Ly‐6 gene induction in a T lymphoma by interferons and interleukin 1, and demonstration of Ly‐6 inducibility in diverse cell types

“…Variants which have lost the surface expression of one chain of the receptor can no longer be activated [18-201. The expression of Ly-6 specificities on the surface of resting purified lymph node and splenic T cells can be dramatically enhanced, or induced de novo following treatments in vitro with interferon (IFN; . Endogenous IFN-y production appears to be directly responsible for the enhanced expression of Ly-6A/E on activated T cells [24]. A marked augmentation in the expression of Ly-6 antigens by T cells was observed 2 days following the in vivo administration of purified IFN-a/ p, or of the IFN-inducing agent, poly(1) * poly(C).…”