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Functional differentiation of human cytotoxic T lymphocytes in the presence of FK 506 and CyA.

1990; National Institutes of Health; Volume: 22; Issue: 1 Linguagem: Inglês

A. Zeevi, G Eiras, Bach Fh, John J. Fung, Satoru Todo, TE Starzl, R Duquesnoy,

Toxin Mechanisms and Immunotoxins

The recognition of antigen is the first step in maturation of effector T lymphocytes. Gromo et al have shown that antigen can trigger a precursor T lymphocyte to respond to additional signals necessary to induce full functional maturation.1,2 Using minimal signals, such as MoAbs to CD2 receptor or MoAbs directed against CD28, they have demonstrated that precursor cytotoxic T lymphocytes (pTcs) can differentiate into pre-effector cytotoxic cells (peTcs). Following the addition of recombinant IL-2 (rIL-2) or IFN-γ, peTcs will acquire cytolytic activity.1,2 Likewise, stimulation with the calcium (Ca2+) ionophore {type:entrez-nucleotide,attrs:{text:A23187,term_id:833253,term_text:A23187}}A23187 drives pTcs into the peTc stage, and rIL-2 induces peTcs to become effector cytolytic cells (eTcs).1 CyA, a T cell-specific immunosuppressive drug, inhibits the generation of effector cells by blocking IL-2 and, to a lesser degree, IL-1 production (reviewed in reference 3). A new immunosuppressive drug, FK 506, has properties similar to CyA, but it is 100 to 400 times more potent.4–9 The strong in vitro inhibitory effect of FK 506 can be demonstrated in primary mixed lymphocyte cultures (MLRs) and secondary proliferation of alloreactive T cells propagated from organ transplant biopsies.6–9 CyA and FK 506 appear to inhibit the transcription of early T cell activation genes, including those coding for IL-2, IL-3, and IFN-γ.3,10,11 These drugs do not affect the proliferation of activated T cells in the presence of IL-2 or the cytolytic effector function.7,8 Little is known of the effect of these drugs on the stages of cytolytic T lymphocyte (CTL) generation. This study was designed to evaluate the effects of these drugs on the stepwise activation, proliferation, and maturation of CTLs induced by {type:entrez-nucleotide,attrs:{text:A23187,term_id:833253,term_text:A23187}}A23187 and rIL-2.