Role of ICOS in Foxp3⁺ Treg responses induced by parasitic helminths
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Date
30/11/2012Author
Redpath, Stephen A.
Metadata
Abstract
Helminth parasites excel at subverting the host’s immune regulatory pathways resulting in
immunosuppressed hosts harbouring chronic infections. This immune suppression forms a
major barrier to the acquisition of protective Th2 immunity, both in regard to natural
infections and potential vaccinations. At the same time, immune downregulation plays a
beneficial role in protecting the host from pathology during chronic infection, and
epidemiological links between helminth infections and the amelioration of allergy and
autoimmunity diseases indicate that helminth-induced immune suppression can be
therapeutically applied to the treatment of these conditions. Foxp3+ regulatory T cells
(Treg) play central downregulatory roles in controlling reactivity to self-antigens and
preventing autoimmune diseases, as well as in limiting inflammatory responses during
infection. Helminths induce dominant Foxp3+ Treg responses that play key roles in
inhibiting protective immunity and alleviating immunopathology, and that can protect
against allergic inflammation. Thus, Foxp3+ Tregs are a fundamental mechanism of
immune regulation during helminth infections, and an understanding of the mechanisms
governing the induction of Foxp3+ Treg responses is of principal importance for the design
of both prophylactic helminth treatments and therapies for allergies and autoimmunity.
However, the nature of the T cell co-stimulatory signals driving Treg generation during
helminth infection is largely unclear. Recent evidence suggests that the inducible costimulator
(ICOS) contributes to Treg control of autoimmune inflammation. Further, ICOS
expression is upregulated by Foxp3+ Treg during infection with the filarial nematode
Litomosoides sigmodontis suggesting ICOS is important for Treg during helminth infection.
Therefore, we investigated the role of ICOS in helminth-induced Treg responses.
Similar to L. sigmodontis infection, Foxp3+ Treg increased ICOS expression in response to
infection with the intestinal nematode Heligmosomoides polygyrus and with the blood
trematode Schistosoma mansoni. Functionally, ICOS was required for the optimal expansion of lymphoid Treg numbers during early stage H. polygyrus infection and
following the onset of the acute egg phase of S. mansoni infection suggesting common
pathways for Treg induction by diverse helminth species. Whilst helminth induced
proliferation and activation of Foxp3+ Treg was ICOS independent, ICOS was essential for
Treg survival in settings of homeostasis and helminth infection. In contrast to the lymph
node, Treg responses in the intestinal lamina propria (LP) of ICOS-/- mice were increased
due to expanded natural Treg. Following H. polygyrus infection Foxp3+ Helios- CD4+ T
cells preferentially expanded in wild-type (WT) mice but not in ICOS deficient mice
suggesting ICOS is required for the expansion of adaptive Treg at the site of intestinal
nematode infection.
Functionally, ICOS supports Treg, but not effector T cells (Teff), H. polygyrus induced IL-
10 production suggesting ICOS differentially regulates Treg and Teff. At the H. polygyrus
infection site, ICOS acted to downregulate CD4+ T cell Th2 cytokine production.
Conversely, in the reactive lymph node ICOS signalling promoted Th2 immune responses,
possibly by maintaining the pool of IL-4 secreting type 2 follicular helper T cells. Thus,
ICOS has different effects on Th2 immunity depending on tissue location. Because Th2
immunity governs expulsion of H. polygyrus parasites, the differences in Th2 responses
between lymph node and infection site could explain why ICOS deficiency did not impact
worm burden.
Protective immunity to long-lived helminth infection can be quenched in the initial days of
infection by the action of Treg. Whether Treg expand and suppress protective immunity
during S. mansoni larvae lung transit has not been investigated. We found that in contrast
to H. polygyrus and L. sigmodontis infection, early S. mansoni infection did not induce a
Treg response suggesting other mechanisms are employed for immune subversion.
During the acute egg-phase of S. mansoni infection, Foxp3+ Treg protect the host from damaging egg-induced hepatic immunopathology. Despite reduced Foxp3+ Treg
responses, ICOS deficiency did not impact egg-induced immunopathology.
Thus, ICOS co-stimulation contributes to early expansion and the continued maintenance
of Treg during helminth infection, both in the local lymph node and at the infection site.
ICOS is required for Treg function during helminth infection by promoting IL-10 production,
whilst its contribution to Th2 effector immunity is tissue specific. In addition, ICOS is
dispensable for protective immunity and pathology during helminth infection. As ICOS
controls both positive and negative immune responses and can have opposing roles
depending on tissue location, an understanding of the consequences of these
contradictory effects will be important when considering targeting ICOS therapeutically.