Investigating mechanisms of regulatory T cell function in inflammatory disease
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Date
08/07/2017Item status
Restricted AccessEmbargo end date
31/12/2100Author
Mair, Iris
Metadata
Abstract
Regulatory T cells (Treg) play a crucial role in controlling immune homeostasis.
Several inflammatory diseases including multiple sclerosis and inflammatory bowel
disease have been associated with dysfunctional and/or reduced numbers of Treg.
While several mechanisms of action have been discovered by which Treg can exert
their function, disease-specific Treg requirements remain unknown. The Treg pool
consists of highly diverse subpopulations, indicating that there is a potential to
optimise Treg-targeted therapies if disease-relevant mechanisms can be established.
Microarray data from our lab suggests a marked upregulation of the integrin αv as well
as the IL-33 receptor ST2 in Treg retrieved from the inflamed central nervous system
(CNS) during experimental autoimmune encephalomyelitis compared to peripheral
lymphoid organs. These two molecules were further investigated within this PhD
project with the aim to understand their role in Treg function during chronic
inflammatory disease.
αvβ integrins have been reported to be needed for effector T cell migration to inflamed
sites through binding of extracellular matrix components and are involved in TGF-β
activation by a variety of cell types. Conditional knockout mice lacking the integrin
αv specifically in Foxpγ+ Treg were generated to address the role of αv integrins on
regulatory T cells in inflammatory disease. αv-/- Treg showed a deficiency in activating
latent TGF-β, but were able to suppress responder T cell proliferation in vitro as well
as in vivo. αv-/- Treg were also able to migrate to the inflamed CNS during EAE and
resolve disease. However, αv-/- Treg were detected at significantly lower numbers and
proportions in the inflamed gut during a curative T cell transfer model of colitis; this
led to a quantitative impairment in the ability of αv-/- Treg to cure colitis when
compared to wild-type (WT) Treg. Whether this is a deficit in migration, survival,
proliferation, or Foxp3 stability, remains to be investigated.
IL-33 acts as an alarmin and is best studied as a cytokine released upon tissue damage
that induces a potent type 2 immune response by acting on a multitude of immune
cells. Expression of the IL-33 receptor ST2 on Treg has recently been associated with
positive metabolic parameters in visceral adipose tissue, protection from gut
inflammation, and tissue-restorative function in other inflamed tissues such as injured
muscle or lung. This project showed that in steady state, ST2+ Treg expressed high
levels of several markers which have been associated with potent regulatory function.
When stimulated in vitro, ST2+ Treg showed a better survival and expansion rate
compared to their ST2- counterparts, even more so in the presence of IL-33. T-bet
deficiency in Treg resulted in an increased ST2+ Treg pool, and T-bet-associated
cytokine IFN-γ was found to antagonise IL-33-induced expansion of the ST2+ Treg
pool in a T-bet-independent manner. When ST2+ and ST2- Treg were tested for their
respective suppressive capacity in vivo, ST2+ Treg were able to suppress responder T
cell expansion despite being found only at low numbers in secondary lymphoid organs
compared to ST2- Treg. However, in a curative model of T cell transfer colitis, ST2+
Treg were less capable of controlling the ongoing immune response than ST2- Treg.
A possible explanation for the superiority of ST2- Treg in this setting can be found in
the fact that injected ST2- Treg acquired a distribution of ST2 expression reminiscent
of WT Treg over the course of disease. On the other hand, an increased starting pool
of ST2+ Treg as occurs in T-bet-/- Treg significantly enhanced the capacity of Treg to
control colitis compared to WT Treg. In conclusion, both ST2- and ST2+ Treg are
likely to have a distinct, non-redundant role in suppressing T cell activation in
secondary lymphoid organs and controlling ongoing inflammation in peripheral tissue,
respectively.