Mast cells are essential intermediaries in regulatory T-cell tolerance

Abstract

Contrary to the proinflammatory role of mast cells in allergic disorders, the results obtained in this study establish that mast cells are essential in CD4+CD25+Foxp3+ regulatory T (T(Reg))-cell-dependent peripheral tolerance. Here we confirm that tolerant allografts, which are sustained owing to the immunosuppressive effects of T(Reg) cells, acquire a unique genetic signature dominated by the expression of mast-cell-gene products. We also show that mast cells are crucial for allograft tolerance, through the inability to induce tolerance in mast-cell-deficient mice. High levels of interleukin (IL)-9--a mast cell growth and activation factor--are produced by activated T(Reg) cells, and IL-9 production seems important in mast cell recruitment to, and activation in, tolerant tissue. Our data indicate that IL-9 represents the functional link through which activated T(Reg) cells recruit and activate mast cells to mediate regional immune suppression, because neutralization of IL-9 greatly accelerates allograft rejection in tolerant mice. Finally, immunohistochemical analysis clearly demonstrates the existence of this novel T(Reg)-IL-9-mast cell relationship within tolerant allografts.

Granzyme B is expressed in mouse mast cells in vivo and in vitro and causes delayed cell death independent of perforin

“…40 However, the role gzmB may play in any of these processes is unknown. Recent evidence implicates mast cell-derived gzmB in the inhibition of tumorigenesis.…”

Immunomodulatory mast cells: negative, as well as positive, regulators of immunity

“…Mast cells also contribute to two additional models of immunosuppression 82,83 . Depinay et al 82 reported that the bites of Anopheles mosquitoes can impair the development of antigenspecific T-cell responses in a model of DTH to ovalbumin in mice, but only if mast cells are present in the bitten skin.…”

“…Depinay et al 82 reported that the bites of Anopheles mosquitoes can impair the development of antigenspecific T-cell responses in a model of DTH to ovalbumin in mice, but only if mast cells are present in the bitten skin. Lu et al 83 showed that mast cells were essential for the optimal induction of tolerance to skin allografts, which requires the participation of CD4 + CD25 + FOXP3 + regulatory T cells. Regulatory T cells are a source of IL-9, and IL-9 can mediate the suppression of alloreactive CD8 + T cells and act as a mast-cell survival and/or growth factor (reviewed in Ref.…”

“…Regulatory T cells are a source of IL-9, and IL-9 can mediate the suppression of alloreactive CD8 + T cells and act as a mast-cell survival and/or growth factor (reviewed in Ref. 83 ). Local production of IL-9 (by regulatory T cells and/or other sources) may contribute to the development, and perhaps influence the function, of mast cells within the tolerant allografts.…”

The role and regulation of 11β-hydroxysteroid dehydrogenase type 1 in the inflammatory response

“…Mast cell mediators cause vasopermeability and oedema (Binstadt et al, 2006) and are important recruiters of leukocytes. Moreover, mast cells are essential in the induction of regulatory T-cell tolerance (Lu et al, 2006). Long implicated in human inflammatory arthritis (Woolley, 2003), recent evidence in mice has highlighted a pivotal role of mast cells in the initiation of inflammatory arthritis initiated by immune complex formation (reviewed, (Nigrovic and Lee, 2005)).…”