A Two‐Signal Mechanism for the Induction of Cytotoxic T Lymphocytes

Abstract

Depletion of adherent cells from stimulator and responder lymphocytes by a single filtration through nylon wool columns led to complete abrogation of the cytotoxic response to the stimulating alloantigen. Cytotoxic responses were restored by adding anti-Thy-1 + complement-greated normal peritoneal exudate cells (PEC) syngeneic or allogeneic to the responding population. Alternatively, the response could be reconstituted with costimulator, a lymphokine obtained by stimulation of spleen cells with concanavalin A. Costimulator was not itself cytotoxic and induced few or no cytotoxic T lymphocytes (CL) in the absence of stimulator cells. Costimulator was also more efficient than allogeneic PEC, which in turn were more efficient than syngeneic PEC, in reconstituting the cytotoxic response. The number of CL produced to the activating alloantigen was shown to increase with increasing concentration of costimulator. More interestingly, in the presence of a relatively high concentration of costimulator, CL were also activated to target cells that differ in H-2 haplotype from the stimulating alloantigen. Lysis of the third-party target cells could not be inhibited by cold targets syngeneic to the activating alloantigen. A clonal assay for cytotoxic precursors was used to confirm that CL for the activating alloantigen and CL for the third-party H-2 antigens were derived from different progenitors. Only about 37% of the cytotoxic clones produced were specific for the activating alloantigen. These observations are explained in terms of a two-signal model of CL activation.

Lymphocyte-mediated lysis of tumor cells in vitro antigen-restricted clonal and unrestricted polyclonal effects

“…Furthermore it can be shifted both in vivo and in vitro [16,19,60,63]. Shifts may be caused as a consequence of direct interaction between different lymphocyte subsets and/or by soluble factors [71]. Another lymphocyte subset does not respond with immediate lytic function, but is triggered to enter into the mitotic cycle after encounter with antigens.…”

Natural and activated cytotoxic lymphocytes which act on autologous and allogeneic tumor cells

“…After a few days such mixed cultures develop cytotoxic potential. On the population level the following cytotoxicity systems can be generated in antigen-containing lymphocyte cultures: (1) Enlargement of the specific clone will result in cytotoxicity against (a) cells that carry the stimulating antigen and (b) cells that carry cross-reactive antigens; (2) Transactivation will recruit lymphocytes with other specificities, and thus targets unrelated to the stimulus may be killed if the proportion of lymphocytes with receptors against their antigens is high [28]. Activated lymphocytes kill certain types of targets (some cultured lines, such as K562 and Daudi), independently of antigen recognition.…”

Cyclosporin‐A therapy of pure red cell aplasia in a patient with B‐cell chronic lymphocytic leukemia

“…It has been speculated that CyA decreases abnormal T-gamma cells in association with the return of normal CFU-E growth (22). CyA is known to reduce the production of interleukin-2 (IL-2) from T-helper cells (25)(26)(27), which results in inhibition of proliferation of T-helper and T-suppressor cells (28)(29)(30)(31). Furthermore CyA has been shown to inhibit the growth of B cells of both the T cell-dependent and T cell-independent types (32)(33)(34)(35).…”