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Mechanism of action of cyclosporine A in vivo. II. T cell priming in vivo to alloantigen can be mediated by an IL-2-independent cyclosporine A-resistant pathway.

G M Pereira, J F Miller and E M Shevach
J Immunol March 15, 1990, 144 (6) 2109-2116;
G M Pereira
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J F Miller
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E M Shevach
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Abstract

Cyclosporine A (CsA) inhibits T lymphocyte activation in vitro by blocking at a pretranslational level the production of IL-2 and other cytokines. It is widely assumed that the effectiveness of CsA as an immunosuppressive drug is secondary to a similar mechanism of action in vivo. We have previously demonstrated that certain parameters of T cell activation in the draining popliteal lymph node in response to the injection of alloantigen in the footpad were either completely resistant or enhanced by the administration of CsA. In the present study, we have shown that the mechanism of action of CsA in vivo is identical to that seen in vitro as CsA completely suppressed the induction of IL-2 mRNA as detected in a nuclease protection assay in lymph node cells from alloantigen-primed animals. Nevertheless, T cells from CsA-treated animals appeared to have undergone both priming and differentiation. Thus, upon culture in vitro in the presence of CsA, cells from CsA-treated animals manifested a vigorous proliferative response that could not be inhibited by the addition of a large panel of anti-cytokine mAb. Furthermore, cells from CsA-treated animals demonstrated an enhanced secondary response to the priming alloantigen, which suggests that they had undergone clonal expansion in vivo. Although CTL activity was markedly suppressed in cells from CsA-treated animals, after a 36-h culture in the absence of CsA, CTL activity equivalent to that detected in cells from nontreated animals was present. Collectively, these data support the existence of an alternative IL-2-independent, CsA-resistant pathway of T cell activation/differentiation that may play a prominent role in the generation of certain T effector functions in vivo.

  • Copyright © 1990 by American Association of Immunologists

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The Journal of Immunology
Vol. 144, Issue 6
15 Mar 1990
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Mechanism of action of cyclosporine A in vivo. II. T cell priming in vivo to alloantigen can be mediated by an IL-2-independent cyclosporine A-resistant pathway.
G M Pereira, J F Miller, E M Shevach
The Journal of Immunology March 15, 1990, 144 (6) 2109-2116;

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Mechanism of action of cyclosporine A in vivo. II. T cell priming in vivo to alloantigen can be mediated by an IL-2-independent cyclosporine A-resistant pathway.
G M Pereira, J F Miller, E M Shevach
The Journal of Immunology March 15, 1990, 144 (6) 2109-2116;
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Print ISSN 0022-1767        Online ISSN 1550-6606