Diferenciación y especialización funcional de las células dendríticas de ratón para la inducción de inmunidad innata y adaptativa
Author
López-Bravo Arancibía, MaríaAdvisor
Fernández-Ardavín Castro, CarlosEntity
UAM. Departamento de Biología Molecular; CSIC. Centro Nacional de Biotecnología (CNB)Date
2009-06-23Subjects
Células dendríticas-Tesis doctorales; Inmunidad celular-Tesis doctorales; Biología y Biomedicina / BiologíaNote
Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 23-06-2009Abstract
Research developed in the last years has highlighted the functional specialization of the
different subpopulations of dendritic cells (DCs) for the induction of inmune responses to different
pathogens, although it remained to be solved some issues related to the identification of the DC
subpopulations responsible for the induction of immunity against different virus, bacteria, fungi and
parasites, as well as those implicated in anti-tumoral responses or allergy. In this sense, two important
issues that remain to be addressed in depth are the cooperation between CD8+ DCs and pDCs in the
induction of anti-viral CD8+ T cell responses, and the adquisition of the functional specialization by
DCs responsible for the induction of Th2 responses.
In the first part of this work we have analized the role of the pDCs in the adquisition of the
functional specilization of CD8+ DCs. We have used FLt3L-DCs cultures, were we have found that
three subpopulations of DCs, fenotipically very similar to those present in the mouse spleen (pDCs
and, CD8+ and CD8- cDCs) can be generated. In contrast to previous published data, we found that
the DC subset equivalent to the splenic CD8+ DCs (CD8+-lk DCs) were not able to complete the
differentiation process, as evidenced by their defect in regulating CD8 and DEC-205 expression.
However, they can cross-present antigens, similar to their in vivo counterparts, the CD8+ DC subset.
After stimulation of Flt3L-DCs cultures with CpG, LPS or poly(I:C) we observed the regulation of CD8
and DEC-205 in the CD8+-lk DC subset, but only when stimulated in the presence of pDCs. In this
sense, the production of IL-12 by cDCs generated in the Flt3L-DCs cultures in response to CpG or
LPS also requires de presence of pDCs. In this regard, we have shown that the mechanism by which
pDCs contribute to the regulation of CD8 expression in CD8+-lk DCs is dependent on type I IFN
produced by pDCs. Finally, we propose that type I IFN could be responsible not only of the induction
of the expression of CD8, but also could play a role in confering to the CD8+ DCs subpopulation
the hability to cross-present antigens, to produce fast and efficiently IL-12 in response to microbial
stimuli or the expression of the enzyme IDO, this last one responsible for their tolerogenic potential
in steady state.
In the second part of this work we have analized the effect of IL-4 produced during Th2 inmune
responses on DCs derived from monocytes recruited to the infection site, or to the draining lympnodes.
In this case we have used a different experimental approach based on the differentiation of DCs
from purified monocytes with GM-CSF, in the presence or not of IL-4. The results obtained showed
that IL-4 blocks the capacity of the DCs differentiated with GM-CSF+IL-4 to produce proinflamatory
cytokines, such as IL-12, in response to LPS or CpG, but not in response to Zymosan. In the case
of LPS stimulation, this blockade seems to de dependent of the expression and accumulation of a
negative regulator that, based on the results we have obtained, could be SOCS1, which expression
its strongly induced at mRNA level in the GM/IL-4 MoDCs. In conclusion, the DCs generated from
monocytes recruited to an inflammatory area with a Th2 cytokine profile are not going to be able to
produce IL-12 (cytokine essential in the induction of Th1 responses) after estimulation through a Th1
stimulus, derived from the same pathogen or expressed by a different pathogen.
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