Possible mechanisms controlling bystander effects

Trans-stimulation of spectator T or B lymphocytes and killing of unrelated target cells imply that a signal can be transmitted to these cells independently of the structures involved in specific antigen recognition. Several explanations have been proposed but the exact mechanism controlling this phenomenon is still a matter of debate. In fact, whether there is an essential difference between specific and bystander effects is not clear and, apart from the process of antigen recognition, mechanisms involved in specific cellular responses could also be responsible for bystander responses.

Cytokines

The most accepted explanation for the existence of such nonspecific effects is the secretion of soluble factors - cytokines - by activated T lymphocytes. During the course of an antigen-specific T cell response, activated T lymphocytes release various lymphokines and, in particular, interleukin 2 (IL-2), IL-4, interferon -y (IFN-y) and tumor necrosis factor 3 (TNF(5; lymphotoxin). These lymphokines exhibit nonanti-gen specific, pleiotropic effects. They could act on any other cell present at the site of the immune response. These cells could be T or B lymphocytes, macrophages or target cells for CTLs, provided they are competent to respond to lymphokines (i.e. they express functional surface receptors for these factors). Local effects of such nonspecific factors on neighboring cells not directly involved in the antigen-specific response could explain the involvement of these cells in the overall response: for example, IL-2 could induce the proliferation of T cells and CTLs; IL-4 could transmit activation signals to naive B cells; and IFNy and TNF|3 could prepare target cells for CTL lysis.

Stage of lymphocyte activation

Bystander responses could be restricted to particular subpopulations of T or B lymphocytes that would be more susceptible to nonspecific signals. Of particular interest is the question of whether bystander effects involve cells in a particular stage of activation. Since cytokines are likely to be responsible for bystander effects, expression of cytokine receptors by the reacting cell may be an important key in this phenomenon.

Cell surface antigens

Cell-to-cell contact through specific and nonspecific cell surface molecules is obviously an important feature of antigen-specific responses. Similarly, nonanti-gen-specific cell-to-cell contact could occur during bystander responses. This could involve nonpoly-morphic surface molecules, conserved regions of polymorphic cell surface molecules (including MHC molecules), or molecules induced after stimulation.

Polyclonal B lymphocytes can be stimulated in cultures containing T cells and a T cell mitogen or polyclonal activator (such as anti-CD3 or anti-T cell receptor monoclonal antibodies). Under these conditions, polyclonal B cell proliferation and antibody production are observed. Therefore, when efficient

T cell stimulation is obtained, induction of a B cell response without any added antigen can be observed. In this case, bystander B cell stimulation is thought to be dependent upon T-B cell contact and probably involves recognition of B cell surface molecules by T cells (e.g. CD28/B7 interactions).

Similarly for CTL responses nonspecific attachment of any target cell to a specific cytotoxic T lymphocyte by means of lectins causes the lysis of the target cell independently of antigen recognition.

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