Tours Medical School, Nephrology and Immunology, Tours, France
Keywords: calcineurin inhibitors; dendritic-cell maturation; effects on; IL-2 secretion by dendritic cells; immunology; T-cell activation
It is well known that, depending on their state of maturation, dendritic cells can activate T cells or render them tolerant. Dendritic cells leave the organ in response to inflammatory stimuli after grafting, migrate to secondary lymphoid organs and then mature. Activation of naive T cells by immature dendritic cells induces tolerance. The factors that convert immature or tolerogenic cells into mature or stimulatory dendritic cells therefore represent key points in the immunology of organ transplantation. The precise molecular mechanisms of such maturation are not fully understood. However, transcription factors such as NF-B and p38 MAK kinases have been reported to be involved [1,2].
The recent finding by Granucci et al. [3] that dendritic cells produce IL-2 after microbial challenge led Fierro et al. [4] to suggest the hypothesis that IL-2 appears to be one of the key molecules conferring unique T-cell stimulatory capacity on dendritic cells, perhaps in an autocrine fashion because dendritic cells express functional IL-2R, at least in the mouse [5]. However, this hypothesis has yet to be proven, although IL-2-deficient dendritic cells have impaired capacity to activate alloreactive T cells [5].
Based on this first hypothesis, Fierro et al. [4] formulated a second hypothesis, namely that calcineurin inhibitors, which regulate IL-2 transcription and secretion by T cells, can control IL-2 secretion of dendritic cells and, as a consequence, dendritic cell maturation. These hypotheses are interesting in terms of manipulation of the immune system during grafting in order to induce tolerance of the graft.
Nevertheless, several points have to be viewed with some caution. For instance, it is not yet proven that IL-2 exerts a key control in dendritic cell maturation. It has not been demonstrated that IL-2 transcription and secretion in dendritic cells is NFAT-dependent and regulated by calcineurin and, as a consequence, that calcineurin inhibitors inhibit IL-2 secretion in dendritic cells. In particular, the effects of calcineurin inhibitors on in vitro dendritic cell maturation have not been clearly demonstrated, in contrast to those of steroids, vitamin D3 analogues and mycophenolate mofetil [6]. Tacrolimus seems to have no effect on dendritic cell maturation [79] and the effects of cyclosporin are controversial. A decrease in membrane expression of CD40, CD80 and CD86 has been reported by Lee et al. [10] in mouse bone marrow-derived dendritic cells, but this was not found by Woltman et al. [7] or Szabo et al. [8] in human monocyte-derived dendritic cells. The latter reported normal CD40L or LPS-induced in vitro maturation of dendritic cells in the presence of cyclosporin, with an increase in expression of co-stimulatory CD80, CD86 molecules and of HLA DR molecules. Nevertheless, as they pointed out, cyclosporin and tacrolimus affect dendritic-cell functions, in particular the capacity to induce T-cell proliferation in mixed lymphocyte reactions and IL-12 secretion.
In conclusion, the existence of IL-2 secretion by dendritic cells raises interesting questions and underlines the potential role of calcineurin inhibitors, perhaps not really in dendritic cell maturation, but more probably in dendritic cell functions.
Notes
Correspondence and offprint requests to: Yvon Lebranchu, Tours Medical School, Nephrology and Immunology, Tours, France. Email: lebranchu{at}med.univ-tours.fr
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