Download Leonie Hussaarts Department of Parasitology, Leiden

Leonie Hussaarts
Department of Parasitology, Leiden Immunoparasitology Group
Leiden University Medical Center, Leiden, Netherlands
Keystone – Type 2 Immunity: Initiation, Maintenance, Homeostasis and Pathology
From January 10 to January 15, Santa Fe (New Mexico, USA) was the scientific hub for investigators
of type 2 immune responses. The Keystone conference on Type 2 Immunity was held jointly with
another Keystone meeting: “Pathogenic Processes in Asthma and COPD”. During the 4.5 day
program, participants could attend lectures of both meetings, and were encouraged to interact during
the poster sessions, over meals or during the social hours.
The lectures of the conference on Type 2 Immunity focused on the major advances in the field, and
covered a wide range of topics: Type 2 immune responses were discussed in the context of helminth
infection, wound repair or commensal bacteria, and lectures focused on both adaptive and innate
immune cells and their cytokines. The session I found most interesting was dedicated to the recently
discovered type 2 innate lymphoid cells (ILC2s). The speakers gave a great overview of this
expanding area of research. The field is relatively young, so I found it fascinating to learn that it has
clearly been established that ILC2s play an important role in both the initiation and amplification of
type 2 immune responses.
Participants who were not selected for an oral presentation, could showcase a poster during one of
the three poster sessions. Each session contained posters of both meetings, adding up to about 50
posters per session. During these informal sessions, I exchanged ideas with researchers interested in
topics similar to that of my own PhD project. I presented my own data during the second session. It
was a great experience to discuss my findings extensively with both senior scientists and graduate
students.
Overall, the conference was inspiring and provided an excellent overview of the state of the art in the
field of type 2 immune responses. The informal atmosphere during the poster sessions and social
hours provided a great opportunity to meet (established) researchers. I would like to thank the NVP for
the financial contribution.
Rapamycin and helminth antigens: mTOR-dependent and -independent mechanisms to
condition human dendritic cells for Th2 polarization
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3
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L Hussaarts , HH Smits , G Schramm , AJ van der Ham , GCM van der Zon , H Haas , B Guigas
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and M Yazdanbakhsh
1
Dept. of Parasitology, LUMC, The Netherlands
2
Research Center Borstel, Germany
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Dept. of Molecular Cell Biology, LUMC, The Netherlands
1,3
Recent reports have attributed an immunoregulatory role to the mammalian target of rapamycin
(mTOR), a key protein kinase integrating input from growth factors and nutrients to promote cell
growth and division. Since the mechanisms driving T helper 2 (Th2) polarization remain poorly
understood, we investigated the role of the mTOR pathway in Th2 skewing by dendritic cells (DC).
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Using a co-culture system of human monocyte-derived LPS-matured DC and allogeneic naïve CD4 T
cells, we show that blocking mTOR with the immunosuppressive drug rapamycin reduced the
expression of CD86, CD80 and HLA-DR on DC, and promoted Th2 skewing characterized by
increased IL-4 and decreased IFN-γ levels. We next investigated whether antigens from helminth
parasites, the strongest natural inducers of Th2 responses, affect the mTOR pathway. To this end, we
used Schistosoma mansoni soluble egg antigen (SEA) and omega-1, which is a single molecule
recently identified as the major component in SEA responsible for Th2 skewing. Importantly, in
contrast to rapamycin, neither SEA nor omega-1 reduced the phosphorylation of mTOR’s downstream
targets P70S6 kinase and 4EBP1, suggesting that these antigens do not affect the pathway. In
addition, co-stimulation with SEA and rapamycin promoted a stronger Th2 response than stimulation
with either SEA or rapamycin alone, further supporting the existence of two independent mechanisms
for Th2 polarization. We conclude that conditioning human DC to skew immune responses towards
Th2 can be achieved via an mTOR-dependent and an mTOR-independent pathway by rapamycin and
helminth antigens, respectively. These findings contribute to the understanding of the different modes
and mechanisms by which DC can be accurately modulated for clinical use.
Grant support: EU IDEA (HEALTH-F3-2009-241642)
Rapamycin and helminth antigens: mTOR-dependent and -independent mechanisms to
condition human dendritic cells for Th2 polarization
1
1
2
1
3
1
L Hussaarts , HH Smits , G Schramm , AJ van der Ham , GCM van der Zon , H Haas , B Guigas
1
and M Yazdanbakhsh
1
Dept. of Parasitology, LUMC, The Netherlands
2
Research Center Borstel, Germany
3
Dept. of Molecular Cell Biology, LUMC, The Netherlands
1,3
Recent reports have attributed an immunoregulatory role to the mammalian target of rapamycin
(mTOR), a key protein kinase integrating input from growth factors and nutrients to promote cell
growth and division. Since the mechanisms driving T helper 2 (Th2) polarization remain poorly
understood, we investigated the role of the mTOR pathway in Th2 skewing by dendritic cells (DC).
+
Using a co-culture system of human monocyte-derived LPS-matured DC and allogeneic naïve CD4 T
cells, we show that blocking mTOR with the immunosuppressive drug rapamycin reduced the
expression of CD86, CD80 and HLA-DR on DC, and promoted Th2 skewing characterized by
increased IL-4 and decreased IFN-γ levels. We next investigated whether antigens from helminth
parasites, the strongest natural inducers of Th2 responses, affect the mTOR pathway. To this end, we
used Schistosoma mansoni soluble egg antigen (SEA) and omega-1, which is a single molecule
recently identified as the major component in SEA responsible for Th2 skewing. Importantly, in
contrast to rapamycin, neither SEA nor omega-1 reduced the phosphorylation of mTOR’s downstream
targets P70S6 kinase and 4EBP1, suggesting that these antigens do not affect the pathway. In
addition, co-stimulation with SEA and rapamycin promoted a stronger Th2 response than stimulation
with either SEA or rapamycin alone, further supporting the existence of two independent mechanisms
for Th2 polarization. We conclude that conditioning human DC to skew immune responses towards
Th2 can be achieved via an mTOR-dependent and an mTOR-independent pathway by rapamycin and
helminth antigens, respectively. These findings contribute to the understanding of the different modes
and mechanisms by which DC can be accurately modulated for clinical use.