Pediatric Rheumatology Online
Journal
http://www.pedrheumonlinejournal.org
PEDIATRIC RHEUMATOLOGY LITERATURE
REVIEW FOR 2003: ARTICLES YOU DON’T WANT TO MISS.
REGULATORY T CELLS
Selected
by
Control of regulatory T cell
development by the transcription factor Foxp3. Hori S,
Nomura T, Sakaguchi S: Science 2003, 299:1057-1061.
AND
Foxp3 programs the development and
function of CD4+CD25+ regulatory T cells.
Fontenot JD, Gavin MA,
Rudensky AY: Nat Immunol 2003, 4:330-336.
AND
An essential role for Scurfin in
CD4+CD25+ T regulatory cells. Khattri R, Cox T, Yasayko SA, Ramsdell
F: Nat
Immunol 2003, 4:337-342.
Significance: Immune
tolerance to self-antigens is induced and maintained by a combination of
central and peripheral mechanisms.
Central tolerance is generated primarily in the thymus where
autoreactive T cells are either deleted or made anergic. Tolerance is then maintained in the periphery
by special subsets of “Regulatory” T cells (TR) that are capable of suppressing and keeping immune
responses in check. The CD4+CD25+ subset
of regulatory T cells appears to be of particular importance. However, the
source of these cells and the mechanisms by which they function remain
relatively obscure. These papers provide
some initial insight by showing that Foxp3,
the gene mutated in the severe, systemic, X-linked autoimmune disorders IPEX
(OMIM 304930 in humans) and Scurfy (in mice), is required for the development
of CD4+CD25+ TR in mice. These studies
not only investigate the mechanism of disease leading to IPEX, but also explore
a potential means for re-establishing peripheral tolerance, which may be useful
in the control of autoimmune disorders in general.
Findings: The CD4+CD25+
TR subset makes up approximately 5-10% of the
peripheral CD4+ T cell population in most normal mice and humans. In Scurfy mice, a two base-pair insertion
within the Foxp3 gene leads to a
frameshift mutation, and this results in a truncated protein product. The subsequent phenotype suffers from a
syndrome of severe autoimmunity characterized by
lymphocytic
infiltrates into multiple organs, and death by 3 weeks of age. These papers show that Scurfy mice lack
CD4+CD25+ TR cells, suggesting a role
for Foxp3 in the development and possibly the function of this subset. This role was supported by generation of
transgenic mice expressing supranormal levels of Foxp3, which leads to animals
with decreased T cell numbers overall but markedly increased percentages of
CD4+CD25+ TR cells (15-20% of the CD4+
population) (Khattri et al).
Mating of the Foxp3
transgenic animals to mice lacking CTLA-4 prevented their offspring’s otherwise
rapid demise due to an autoimmune lymphoproliferative disorder similar to that
of Scurfy mice, thus suggesting that the two pathways may intersect. Further evidence for Foxp3’s role in the development
of CD4+CD25+ TR cells was provided by
forcible expression of Foxp3 in naïve CD4+ T cells by retroviral transduction
(Hori et al & Fontenot et al.). Cells transduced with Foxp3 developed a
surface phenotype similar to endogenous TR cells including expression of CTLA-4 and GITR. Like endogenous TR cells, they were able to suppress other activated T
cells in a cell-contact dependent fashion; however, their effect was not as
potent, suggesting that Foxp3 is necessary but not sufficient for development
of full regulatory activity. The most exciting
capability of the Foxp3 transduced T cells was their ability to suppress
disease when adoptively transferred into mice with autoimmune enteropathy
portending a possible role for Foxp3 in gene therapy for autoimmune diseases in
the future (Hori et al.).