Biology Reference
In-Depth Information
Cytokines involved in Th17/Treg differentiation
Transforming growth factor-
β
TGF-β has wide-ranging regulatory effects on cellular processes including
proliferation, differentiation, maturation, and cell survival
[119]
. It is pro-
duced by platelets, myeloid cells, and T cells
[120,121]
. TGF-β provides sig-
nals to naïve T cells, which induce differentiation toward either a regulatory
(FOXP3
+
) phenotype or a Th17 phenotype, depending on the other cyto-
kines present. It also inhibits the release of proinflammatory cytokines by
macrophages
[122]
[123]*
.
Several preclinical studies have also indicated that TGF-β has a specific
role in inhibiting T-cell responses to alloantigen in the transplant setting
[124,125]
. Preclinical transplant models involving blockade of TGF-β con-
firm the role for this cytokine (in combination with IL-10) in protecting
transplant recipients from aGVHD, but that, conversely, TGF-β can promote
cGVHD late after transplant
[126]
Additionally, this study demonstrated
that TGF-β was produced predominantly by donor T cells immediately
post-transplant and during aGVHD, but by myeloid cells in the context of
cGVHD. Presumably, this duality exists because during early inflammation
the immunoregulatory effects of TGF-β are dominant, whereas later, it plays
an important role in promoting the fibrosis that is characteristic of cGVHD.
The impact of other cytokines during both periods is also important to con-
sider, given that TGF-β acts in delicate balance with other cytokines to drive
either Th17 or Treg differentiation.
372
Of note, TGF-β has been measured in the clinical setting and it has been
shown that it is in fact present in higher levels in patients with grades 0-I
aGVHD compared to those with grades II-IV
[127]
.
IL-6
IL-6 is a pleiotropic proinflammatory cytokine, which was initially discov-
ered because of its capacity to promote B-lymphocyte differentiation into
plasma cells, though it is now known to perform a variety of other functions.
It is produced by monocyte/macrophages, as well as mature DCs, though
not exclusively by these cell types, with production also demonstrated by
T and B lymphocytes, as well as fibroblasts and other nonhematopoietic
cells. It belongs to the glycoprotein 130 (gp130) family of molecules, which
also includes IL-11, ciliary neurotrophic factor, leukemia inhibitory factor,
oncostatin M, cardiotrophin-1, cardiotrophin-like cytokine, and IL-27.
IL-6 acts to promote T-cell proliferation, the differentiation of cytotoxic
T-lymphocyte populations, and Th17 development (and conversely inhibits
Treg production) when signaling in concert with TGF-β
[128,129]
.
IL-6 signaling occurs after either direct binding of the cytokine to the
membrane-bound form of the receptor (which then dimerizes with the
gp130 molecule to acquire signaling function) or by coupling of soluble
IL-6 with the soluble form of its receptor and subsequent binding of this
cytokine:receptor complex to cells expressing gp130. This process is called
* Chapter 12 is devoted to the discussion of regulatory T cells in GVHD and GVL effects.
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