2026-08-29T08:18:07Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/72362024-09-27T09:44:54Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605
Repisalud
advisor
Gonzalez-Granado, Jose Maria
author
Toribio-Fernandez, Raquel
2019-02-25T14:08:52Z
2019-02-25T14:08:52Z
2019-01-18
10.4321/repisalud.7236
http://hdl.handle.net/20.500.12105/7236
A-type lamins (lamin A/C) are intermediate filament proteins that conform with B-type lamins the
nuclear lamina (NL). The NL is localized just below the inner part of the nuclear envelope. Thus, the
NL interacts with chromatin and transcription factors, modulating epigenetics and gene expression,
among other essential functions as cell migration, proliferation, differentiation, and cell cycle
progression. However, the most well-known function of lamin A/C is the maintenance of nuclear
structure. Little information is known about the expression and function of A-type lamins in immune
cells, and specifically in CD4+ T lymphocytes. CD4+ T-lymphocytes are one of the main components of
the adaptive immunity, a very complex and a highly specialized immune response that defends the
organism against infections. These lymphocytes need to interact through their T-cell receptor (TCR)
with an antigen-presenting cell to become active, forming what is called immune synapse (IS). Once the
TCR recognizes an antigen, lamin A/C has been shown to be expressed in the CD4+ T-cell, enhancing
a proper IS formation and thus CD4+ T-cell activation. Due to its important role in T-cell activation, we
hypothesized that lamin A/C might have also a role in proliferation, differentiation and effector function
of CD4+ T lymphocytes. We have corroborated that lamin A/C significantly enhances T-cell activation
in vivo, but it does not regulate T-cell proliferation. Interestingly, our results indicate that lamin A/C
significantly determines the T-helper (Th) phenotype commitment. Hence, we have observed in vitro
and in vivo that lamin A/C enhances Th1 differentiation, without affecting Th2 and Th17 phenotypes. Moreover, lamin A/C improves Th1 cells effector function against vaccinia virus (VACV) and
Leishmania major infections in mice by enhancing CD4+ T cell cytotoxic capacity and Th1 effector
response. Furthermore, Lmna-/- CD4+ T-cells protect from inflammatory bowel disease (IBD)
development in mice enhancing regulatory T-cells (Treg) differentiation, and improving their
suppressive function. The molecular mechanism by which lamin A/C determines Th fate is the
upregulation of the Th1 master regulator (T-bet), and the downregulation of Treg master regulator
(Foxp3). In more detail, lamin A/C epigenetically modifies the T-bet promoter enhancing its gene
transcription. However, lamin A/C does not induce epigenetic changes in Foxp3 promoter. Besides, it
is known that retinoic acid (RA) can regulate lamin A/C expression in leukocytes. Additionally, it has
been described that CD103+ dendritic cells (DCs), mainly located in the mesenteric lymph nodes, release
RA. We have demonstrated in mesenteric lymph nodes that the RA released by CD103+ DCs
downregulates lamin A/C in CD4+ T-cells upon antigen recognition, enhancing Treg differentiation. In
contrast, in spleen and peripheral lymph nodes, CD103- DCs are predominant and do not produce RA,
facilitating lamin A/C expression in CD4+ T-cells upon antigen recognition, and thus, Th1
differentiation. By this physiological mechanism, lamin A/C levels can be modulated in different
anatomical sites, in accordance with immunological requirements to control naïve T cell differentiation. Altogether, our findings set A-type lamins as key regulators of Th differentiation, and thus potential
therapeutic targets for IBD and infectious diseases.
eng
lamin A/C
T-cell
immune response
Th1
Biological and pathological role of A-type lamins in T-cell mediated immune response
doctoral thesis
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URL
https://repisalud.isciii.es/bitstreams/c1dab32a-2ec3-49b2-9f22-ef0f820fdd07/download
File
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Tesis_Raquel Toribio.pdf
URL
https://repisalud.isciii.es/bitstreams/ffd86cae-4d83-49b4-8664-df9ec2eb5af2/download
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Tesis_Raquel Toribio.pdf.txt