Natural CD4 CD25 FOXP3 regulatory T cells in graftversus-host disease - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 252

GVHD would bring Treg cell numbers below a critical threshold that usually
allows them to maintain gut-associated DC in a tolerogenic state and thus
initiate a negative feedback loop culminating in increased inflammation. In
this scenario, cotransplantation of high numbers of donor Treg cells would
then primarily lead to a normalization of Treg cell numbers in MLN (and
probably in other barrier-associated LN) and thereby reestablish their con-
trol over DC function ( Figure 12.1 ).

In addition to these early and direct effects, cotransplanted donor Treg cells
also mediate long-lasting effects in that they support the process of general
immune reconstitution in the host. This is mediated most likely via preven-
tion of tissue destruction in the thymus and other lymphoid organs that are
indispensable for reconstitution of an intact and functional immune system
[115-117] . Additionally, it could be shown that Treg are critically involved in
the development of a diverse T cell repertoire during reconstitution from
lymphopenia by restricting T cell clones with a high lymphopenia-induced
proliferation potential [118] .

Not all Tconv cell-mediated effects in allogeneic hematopoietic SCT are
detrimental, as mature T cells in the graft are in large part responsible for
the GVL effect in patients with hematological malignancies. A reduced inci-
dence of disease relapse in patients experiencing at least some degree of
GVHD as well as concomitant induction of GVHD and partial or complete
disease regression after donor lymphocyte infusion (DLI) highlights the
fact that broadly expressed major and minor histocompatibility antigens
elicit both GVH and GVL reactions. It was thus a major concern that the
cotransplantation of large numbers of donor Treg cells with the BM graft
would significantly impede this beneficial effect. However, it was shown in
a number of murine studies investigating GVHD and GVL simultaneously

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FIGURE 12.1
Threshold model for the roles of nTreg and iTreg in GI GVHD. Under steady-state conditions a sufficient number of thymus-derived natural Treg (nTreg) are present in
MLN to keep local DC in a tolerogenic state by inhibiting the upregulation of costimulatory (CD80/CD86) and MHC class II molecules and by stimulating IDO expression.
In addition, DC secrete retinoic acid (RA) that, in combination with locally produced TGF- β , supports the differentiation of naïve CD4 + Tconv cells into Foxp3-expressing
iTreg. A positive feedback loop via nTreg- and iTreg-produced IL-10 stabilizes this homeostatic state. In GVHD, nTreg cell numbers drop below a threshold and are no
longer able to modulate DC. These convert from a tolerogenic into an immunogenic state and now support the differentiation of naïve Tconv into inflammatory effector
T cells (Teff). Impaired iTreg induction and increased secretion of proinflammatory cytokines (e.g., IFN- γ ) by Teff cells further exacerbates local inflammation. The cotrans-
fer of high numbers of nTreg cells with the BM graft may keep nTreg cell numbers in MLN above a critical threshold level and thereby prevent the switch of DC to
an immunogenic state and thus limit inflammation (and GVHD) in the GI tract.