Evidence for direct linkage between antigen recognition and lytic expression in effector T cells.

Abstract

The mechanism of cytotoxicity mediated by thymus-derived (T) lymphocytes can be divided into two phases, one of antigen recognition, the other the cytolytic event. The antigen recognition phase shows immunological specificity and consists of the interaction of target cell antigen with the effector cell's antigen receptor site (1-3). The relationship between this accomodation and the subsequent killing process is unknown.Conceptually, one could view the role of the T cell's antigen receptor in one of two ways. On the one hand, the receptor could serve simply as a bridge, bringing the target cell into close approximation with the effector cell. It could be that the duration of this contiguity is an essential element in rendering the target cell susceptible to lytic attack. In this model, activation of the killing mechanism would be independent of antigen recognition, either because the differentiated effector cell can cause lysis without requiring activation, or because the "triggering" required occurs at sites of cell-cell interaction which have no linkage with the antigen receptor.On the other hand, the receptor site might play a much more central role in a T cell's lytic attack, and there might be a direct linkage between antigen binding and stimulation of the lytic mechanism. This model would suggest that the killer cell only expresses its lytic potential after accomodation of its antigen receptor.In both hypotheses, the antigen receptor site endows specificity to T-cellmediated lysis, but the models assign markedly different roles to the receptor and view cytolysis in distinctive ways. The experiments reported here were designed to decide between these alternative concepts. The studies were based on a recent observation that lytically active T cells can themselves serve as targets for other effector T cells (4, 5). We asked a rather simple question: if one mixed effector cells of two specificities, selected so that antigen recognition could occur only in one direction (Fig. 1), did killing occur in one or both directions? Our findings provided an unequivocal answer: cytolysis proceeded only in the direction of antigen recognition. The effector cell with its antigen receptor site

Resistance of cytotoxic T lymphocytes to the lytic effects of their toxic granules.

“…This limited-release model is consistent with one-way killing of target CTLs by other (aggressor) CTLs, especially in an allogeneic MLC where the fraction of aggressor CTLs is not defined (30). At high aggressor/target ratios, several aggressor CTLs might be able simultaneously to adhere to and deliver their individually controlled release of toxic granules on a single hapless target CTL.…”

“…The findings extend several other observations that CTLs make poor targets for other CTLs (12,27) . Yet many other studies have demonstrated that, under some circumstances, a CTL can be lysed when it is recognized by other CTLs (28)(29)(30), a phenomenon referred to as one-way killing …”

Mechanisms of suppression of cytotoxic T-cell responses in murine lymphocytic choriomeningitis virus infection.

“…Since LCM virus is not overtly cytopathic for lymphoid cells (4,5), direct killing of T cells by virus seems an unlikely explanation. One possible mechanism is based upon findings that one cytotoxic T cell can kill another (29)(30)(31), provided the former has receptors complementary for antigenic patterns on the latter (30). The presence of a high level of virus in the environment of responding cytotoxic T cells specific for LCM virus-induced antigenic patterns could result in cytotoxic cells or their precursors, becoming infected and displaying antigenic patterns complementary for their own antigen receptors.…”

“…$ Significantly greater lysis (P < 0.001) than with the relevant control of normal spleen cells on same target at the same effector:target ratio. § P < 0.01. specific cytotoxic T cells are themselves infected, display virus-induced antigen patterns complementary for their own antigen-receptors, and thus either commit suicide or kill each other (29)(30)(31). To test formally whether LCM virusinfected T cells are susceptible to T-cell-mediated lysis, spleen cells from LCM virus congenital carrier or from normal mice were stimulated in vitro with the T-cell mitogen Con A (32) for 5 days and then used as labeled target cells, either infected or uninfected, respectively.…”

Inhibition of Cytotoxic T Lymphocytes by a Schistosome-Derived Inhibitory Factor Is Independent of an Inhibition of the Production of Interleukin 2

“…CTL, however, have to bind to their target through their antigen receptor to become efficient [23,24] and it is possible that this signal of activation, or a posterior event like the modification of cyclic nucleo tide levels or the delivery of the lethal hit share a SDIF-sensitive process with the mitotic cycle. It is in teresting to note along this line that quercetin, a sub stance related to disodium cromoglycate [25], and some monoclonal antibodies [reviewed in ref.…”