The multichain interleukin-2-receptor: A target for immunotherapy of patients with adult T-cell leukemia, autoimmune disorders and individuals receiving allografts

Abstract

Antigen-induced activation of resting T cells induces the synthesis of interleukin-2 (IL-2), as well as the expression of specific cell surface high-affinity receptors for this lymphokine. There are at least two forms of the cellular receptors for IL-2, one with a very high affinity and the other with a lower affinity. We have identified two IL-2-binding peptides, a 55-kD peptide reactive with the anti-Tac monoclonal antibody and a 75-kD non-Tac IL-2-binding peptide. Cell lines bearing either the p55 (Tac) or the p75 peptide alone manifested low- to intermediate-affinity IL-2 binding, whereas cell lines bearing both peptides manifested high- and low-affinity receptors. Fusion of cell membranes from low-affinity IL-2-binding cells bearing the Tac peptide alone with membranes from a cell line bearing the p75 peptide alone generated hybrid membranes bearing high-affinity receptors. We propose a multichain model for the high-affinity IL-2-receptor in which both the p55 Tac and the p75 IL-2-binding peptides are associated in a receptor complex. An additional 90–100-kD peptide may also participate in the multi-subunit high-affinity form of the IL-2-receptor. The p75 peptide is the receptor for IL-2 on large granular lymphocytes and is sufficient for the IL-2 activation of these cells. In contrast to resting T cells, the activated T cells in certain neoplasias of mononuclear cells, select autoimmune disorders and in organ allograft rejections express the Tac antigen. Specifically, human T-cell lymphotrophic virus Type I (HTLV-I)-associated adult T-cell leukemia cells constitutively express large numbers of IL-2 Tac receptors. A 42-kD tat protein encoded predominantly by the pX region of HTLV-I may play a role in directly or indirectly increasing the transcription of the 55-kD Tac IL-2-receptor gene. To exploit the fact that IL-2-receptors are present on abnormally activated T cells but not on normal resting cells, clinical trials have been initiated involving patients with neoplastic or autoimmune disorders as well as those receiving organ allografts. These patients are being treated with unmodified anti-Tac, with anti-Tac conjugated to truncated Pseudomonas toxin, with isotopic ( 212Bi and 90Y) chelates of anti-Tac and with recombinant ‘humanized’ anti-Tac.