Natural CD4 CD25 FOXP3 regulatory T cells in graftversus-host disease - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 243

In 1995 Shimon Sakaguchi and his colleagues brought suppressor T cells
back en vogue [1] . Using a model system in which thymectomy in neonatal
mice causes autoimmunity in various organs (e.g. ovary, stomach, thyroid
gland and testis), they showed that the transfer of mature T cells from syn-
geneic adult mice prevented this autoimmune syndrome. Importantly, they
found that CD4 + T cells that coexpress CD25 (the IL-2 receptor α-chain)
are responsible for this effect. The functional characterization of this T cell
subpopulation revealed that they are anergic, as they do not induce any
inflammatory response themselves, and suppressive, as they inhibit the
activation and proliferation of CD25-negative conventional T cells (Tconv)
[1] . These initial experiments already revealed key features of natural reg-
ulatory T (Treg) cells, namely that they are generated in the thymus, that
they are exported from the thymus with a slight delay compared to Tconv
(autoimmunity developed only if thymectomy was performed up to day 3
of life), that they seem to be long-lived in the periphery (since thymectomy
after the first week after birth does not cause autoimmunity), and that they
are suppressive, as their adoptive transfer prevented autoimmunity despite
the presence of autoreactive Tconv cells. The identification of phenotypic
markers, namely their constitutive coexpression of CD4 and CD25, per-
mitted for the first time the specific identification and isolation of viable
suppressor cells for their further in vitro and in vivo examination. Although
this marker combination is not exclusive for Treg, it represented signifi-
cant progress and prompted a plethora of studies exploring the role of Treg
cells in the regulation of the immune system and their function in health
and disease. Among those, some groups studied Treg in models of GVHD,
because suppressor cells that do not initiate immune responses them-
selves but suppress inflammatory T cell populations seemed an attractive
tool to modulate GVHD without completely eradicating alloreactive donor
T cells. Results from these experimental models and the efforts undertaken
to unravel the role of natural Treg in clinical SCT are summarized in this
review.

246

Treg biology

Thymus-derived, natural Treg cells play a decisive, nonredundant role in
maintaining immune homeostasis. Since Sakaguchi's seminal experiments
described above, CD4 + CD25 + Treg became one of the most intensively
investigated and characterized immune cell populations. Despite all these
efforts, however, no Treg cell-specific surface marker has been detected to
date—a fact that has strongly hampered the development of isolation strat-
egies for Treg cells, especially for clinical use (see below).

In 2003 three groups independently identified FOXP3, a member of the
forkhead/winged-helix family of transcription factors, as the lineage-defin-
ing transcriptional master regulator in Treg cells [2-4] . First hints came from
the mutant mouse strain “scurfy,” which possesses a loss-of-function muta-
tion in the Foxp3 gene located on the X chromosome. The CD4 + T cell com-
partment of hemizygous males displays a hyper-reactive phenotype and, in
consequence, the mice develop a lymphoproliferative disease that leads to
death 3 to 4 weeks after birth [5] . In parallel, a loss-of-function mutation
in the human FOXP3 gene, the ortholog of mouse Foxp3, was identified