Direct activation of resting T lymphocytes by human T-lymphotropic virus type I

Abstract

The mitogenic or antigenic stimulation of T lymphocytes in the presence of accessory cells results in the synthesis of interleukin-2 (IL-2), which, on interacting with de novo synthesized receptors on the membrane, induces the proliferation and differentiation of T cells. T lymphocytes are the preferential target cells of human T-lymphotropic virus type I (HTLV-I). This virus was isolated from leukaemic cells of patients with adult T-cell leukaemia. No viral transcription was detected in these leukaemic cells, indicating that consistent expression of HTLV-I is not needed for maintenance of the neoplastic state. After a short time in culture, these leukaemic cells produce viral particles which immortalize normal T cells. Hence, HTLV-I might be an important agent not only in the development, but also in the initiation, of this lymphoproliferative disease. This possibility was sustained by our previous observations indicating that normal T lymphocytes incubated with HTLV-I are able to form colonies in soft agar, seven days later, in the absence of exogenous IL-2. These results led us to explore further the immediate effects of viral infection on purified resting T lymphocytes. Here, we present evidence that HTLV-I is able to activate T lymphocytes. Indeed, binding of viral particles to these cells induces IL-2 production and IL-2 receptor expression, and triggers T-cell proliferation. This initial activation, which appears to be independent of accessory cells, may be relevant in understanding the role of HTLV-I in the aetiology of adult T-cell leukaemia.

T-cell activation by autologous human T-cell leukemia virus type I-infected T-cell clones.

“…As purified HTLV-I virlops have been reported to directly activate T cells (15,16), we tested a purified HTLV-I virus preparation ( Table 4). The purified virus induced a moderate degree of proliferation that could not be blocked by a mAb (0.5a) to gp46 or by a high-titer HTLV-I antiserum.…”

“…A large fraction of T-cell clones were found to be infected (15), which raises the issue of nonspecific inhibitory effects not related to anti-HTLV-I antibodies. As HTLV-I virus preparations induced only a moderate degree of T-cell proliferation that was blocked by mAbs to both CD2 and LFA-3 but not by a mAb to gp46, it is possible that the induced proliferation is caused by contaminating T-cell membranes containing LFA-3, the ligand for CD2 (10,18).…”

Envelope Is a Major Viral Determinant of the Distinct In Vitro Cellular Transformation Tropism of Human T-Cell Leukemia Virus Type 1 (HTLV-1) and HTLV-2

“…Another plausible explanation is that Env-1 and Env-2 may trigger specific postentry signaling pathway(s) that promote HTLV-mediated cellular transformation in different T-cell types. Env-1 gp46, in conjunction with the CD2/LFA-3 activation pathway, is mitogenic to resting T lymphocytes (15,21,36). Furthermore, two recent reports indicated that HTLV receptor expression is induced by T-cell activation and possibly plays a role in the immunobiology of activated T cells (46,50).…”

CD3-dependent lymphocyte activation by human T cell leukaemia virus type I-producing T cells

“…Initial observations suggested that virion-associated Env protein gp46 was a T cell mitogen (Gazzolo et al, 1987). Subsequent studies could not validate those observations, but instead demonstrated that the mitogenic activity was T cell-associated and mediated by cellular glycoproteins (Wucherpfennig et al, 1992;Kimata et al, 1993).…”