Regulatory interactions among autologous T cell clones. Human bifunctional T cell clones regulate the activity of an autologous T cell clone.

In contrast to the ease of cloning and characterizing, at the molecular level, helper and cytotoxic T cells, suppressor T cells remain an enigma, and their existence as discrete entities is being increasingly challenged. Here we review evidence that CD4+ regulatory clones, capable of expressing both helper and suppressor functions, may account for much of the suppressor function. It is suggested that a single T cell clone, depending on the signals it receives from its environment, may release either helper or suppressor cytokines. Studying such clones under defined conditions (providing suppressor signals), may preclude detection of their helper capacity. Since some therapeutic approaches in various human diseases are based on the manipulation of helper and suppressor functions, the question whether committed suppressor cells exist has important practical implications in medicine.

Specific interactions between a human CD4+ clone and autologous CD4+ bifunctional immunoregulatory clones.

The cellular communications between a human CD4+ clone and autologous CD4+ clones induced with the first clone are described. The autoreactive clones proliferated after stimulation with the inducer clone, but not after stimulation with autologous clones expressing irrelevant specificities. The inducer clone markedly lost its ability to interact with the autoreactive clones after the modulation of its T-cell receptor. The proliferation of the autoreactive clones stimulated with the inducer clone was blocked by anti-DR monoclonal antibody. Collectively, these findings indicate that the autoreactive clones recognize idiotypic-like determinants on the receptor of the inducer clone in conjunction with DR antigen. The regulatory activity of the autoreactive clones was assayed by co-cultivation with their target inducer clone. The autoreactive clones were not committed to a single program, they could either suppress or enhance the proliferation of the target cells depending on the state of activation of the target cells. Activated target cells were suppressed whereas non-activated cells were enhanced. It is predicted that antagonistic cytokines released from the autoreactive clones exert differential effects on the target clone.

Interactions between autologous T cell clones.

A human CD4 clone (Mx9/9) using the V beta 8 receptor was used as antigen to generate autologous clones (termed anti-Mx9/9 clones) which proliferate in response to this clone, but not other autologous clones. This was used as an experimental model to explore the specific interactions between autologous T cells. Anti-HLA-DR monoclonal antibodies inhibited the response of the anti-Mx9/9 clones, suggesting that these clones recognize their target antigen in association with HLA-DR. Because of the specificity of the anti-Mx9/9 clones for the initiating clone (Mx9/9), but not any other autologous V beta 8- or V beta 8+ CD4 clones, the target antigen seems to be part of the T cell receptor, but not V beta 8 itself. However, the anti-Mx9/9 clones responded also to the autologous EBV line, and thus the target antigen is not known. The regulatory activity of the anti-Mx9/9 clones was assayed by coculture with their target clone. A variety of responses were seen, both inhibitory and stimulatory, which varied depending on the "conditions" of the T cell used. These results suggest that T cells interact in a complex network, perhaps as complex as the regulatory interactions between antibody molecules and B cells.

T-cell clone anti-clone interactions. Effects on suppressor and helper activities.

An experimental model of two interacting clones of T cells is described, which may be used for defining and exploring the T-cell immunoregulatory network. Mx9/9 is a CD4 clone bearing an antigen receptor recognized by the Mx9 anti-V beta 8 monoclonal antibody (MoAb). Anti-V beta 8 MoAbs activate and induce cell proliferation of this clone. Autologous clones were raised against Mx9/9 cells using the peripheral blood mononuclear (PBM) cells of the Mx9/9 clone donor (PBMjm). Some of these cloned anti-clone cells proliferated after stimulation with irradiated Mx9/9 cells, but not after stimulation with other autologous cloned T cells or heterologous PBM, suggesting that these clones recognize the T cell receptor (TCR) of the Mx9/9 cells. The proliferation of the Mx9/9 stimulated cloned anticlone cells was blocked by anti-class II MoAbs, indicating that the autoreactive clones recognize their target antigen in conjunction with HLA Class II products. The ability of clone Mx9/9 to proliferate after stimulation with anti-V beta 8 MoAb was inhibited when clone 121 cells were added to the cultures. However, clone 121 lost its suppressor function after 4 months in culture and instead gained the ability to enhance the proliferation of Mx9/9 cells in the presence of anti-V beta 8 MoAb. In contrast, clone 18 lacked suppressor activity at the early stage of the study but later acquired this function. We conclude that some autoreactive clones are not fully committed and may express more than a single function. Such cells cannot therefore be designated as 'suppressor cells', although they expressed suppressor potential at certain stages.

Interleukin-2 can prevent and reverse antigen-induced unresponsiveness in cloned human T lymphocytes.

The exposure of human T-cell clones to supra-immunogenic concentrations of peptide antigen in the absence of accessory cells induces antigen-specific unresponsiveness. Using this model we have investigated the ability of cytokines to modulate the induction of, or reversal of, T-cell tolerance. Our findings demonstrate that interleukin-2 (IL-2), but not interferon-gamma (IFN-gamma) or interleukin-1 (IL-1), is able to inhibit the induction of T-cell unresponsiveness in a dose-dependent fashion. Moreover, IL-2 was able to reverse established antigen-dependent T-cell unresponsiveness. In order to determine if modulation of IL-2 receptors is able to induce or abrogate unresponsiveness, the T cells were treated with anti-Tac antibody alone or together with tolerizing concentrations of antigen. Anti-Tac antibody was neither able to induce nor inhibit the induction of tolerance. The application of this model in the manipulation of immune responses is discussed here.

Cellular immunity to herpes simplex virus in man. VII. K-cell activity to HSV1 infected target cells in disease.

Herpes simplex virus-infected target cells, sensitised with antiviral antibody can be lysed by non-immune human lymphocytes (K-cells). This antibody dependent cell mediated immunity (ADCC) is a very efficient technique for destroying foreign target cells and may play a role in maintaining the localization of recurrent herpetic infections. We have used 51Cr labelled herpes virus infected target cells to examine the K-cell activity of peripheral blood lymphocytes in patients who have either malignant reticuloendothelial diseases or who are receiving cytotoxic and steroid therapy for other reasons. K-cell activity was generally within the normal range in such patients and was surprisingly stable despite the occasional use of relatively large doses of cytotoxic agents. It is unlikely, therefore, that a defect in ADCC is responsible for the dissemination of herpes virus infections that may be seen in association with the above drugs and diseases.