Post on 18-Aug-2020
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Práctica ProfesionalPRODUCCIÓN EDITORIALP. Profesional. Sofía Bustamante Leguia, Universidad de Tarapacá.
REVISTA DE CIENCIAS DE LA SALUD Y MEDICINA
ReCISAM
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Indice
• ReCISAM • Objetivos• Práctica• Etapa 1
• Anexos• Etapa 2
• Anexos• Etapa 3
• Anexos• Etapa 4
• Anexos• Etapa 5
• Anexos
3 pag. 3 pag.4 pag.4 pag.
5-25 pag.26 pag.27 pag.26 pag.
28-29 pag.30 pag.
31-32 pag.30 pag.33 pag.
REVISTA DE CIENCIAS DE LA SALUD Y MEDICINA
ReCISAM
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ReCISAM La Revista de Ciencias de la Salud y Medicina es un medio de difusión científica que nace el año 2014 al interior de la Facultad de Ciencias de la Salud de la Universidad de Tarapacá. Publicará trabajos originales sobre temas de interés en la Ciencias de la Salud, Medicina y Ciencias afines.
ObjetivosPromover la creación, divulgación e intercambio de información científica y técnica, entre profesionales, científicos y estudiantes que se desempeñan en las áreas de Ciencias de la Salud, Medicina y Ciencias afines.
Ser una revista científica internacional de reconocido
prestigio, calidad e impacto en las áreas de Ciencias de la Salud, Medicina y Ciencias afines.
Ser una revista que contribuya a la generación, promoción y transferencia científico-tecnológica de conocimientos a la comunidad científica regional, nacional e internacional.
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PrácticaLa practica profesional consistía en distintas actividades, como la edición y elaboración de el numero 3 de la Revista de Ciencias de la Salud “ReCISAM”, actualización de textos en HTML, creación de afiches publicitarios y elaboración de propuestas de diagramación para la aplicación futura de esta Revista de Ciencias de la Salud.
Etapa1La primera etapa consistía en la diagramación de los 15 artículos de la revista. Cada articulo debía estar correctamente editado, las imágenes debían encontrarse en una buena calidad, las tablas debían ser adaptadas al diseño de la revista y las referencias debían ser comprobadas.
A continuación 1 Artículo.
Rev. cienc. salud med. Volumen 3, Número 2, Mayo de 2016.
THE HALLMARK OF CD28, CD2, CD40L AND LFA.1 COSTIMULATORY MOLECULES IN THE MODULATION OF T LYMPHOCYTE RESPONSE
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ARTÍCULO DE REVISIÓN
THE HALLMARK OF CD28, CD2, CD40L AND LFA.1 COSTIMULATORY MOLECULES IN THE MODULATION OF T
LYMPHOCYTE RESPONSE
Eduardo Parra1
Luis Gutiérrez2
Andrea Larrazábal1
1.Escuela de Medicina, Facultad de Ciencias de la Salud, Universidad de Tarapacá, Avenida General Velásquez 1775, Arica, Chile.2.Universidad Arturo Prat, Avenida. Arturo Prat 2120, Iquique, Chile.
Correo autor: eparra@uta.cl
RESUMEN La activación de las células T es fundamental para la coordinación de las respuestas inmunes específicas contra patógenos invasores. La iniciación de estas respuestas requiere co-estimulación a través del receptor de las células T (TCR) y de otras moléculas co-estimuladoras ubicadas en la superficie de estas células. La participación de estas señales secundarias son cruciales, ya que la activación de las células T a través del TCR en ausencia de la señal 2 induce energía. A pesar del gran número de moléculas conocidas en la actualidad, cuatro tipos de interacción ligando receptor han sido ampliamente estudiados demostrando ser de mayor importancia en la activación de las células T: CD2/LFA-3, LFA-1/ICAM-1, CD28/B7-1/2, CD40L/CD40. Estas vías parecen inducir distintas funciones efectoras en los subgrupos de células T creando a partir de allí el perfil de la respuesta inmune. Es así, que la vía CD2/LFA-3 parece jugar un papel central en la expansión de las células vírgenes T ayudantes, caracterizándose por una función de adhesividad fuerte y por inducir la producción de TNF-α y IFN-g, pero es un mal inductor de la IL-2. Las células de memoria por otro lado parecen responder preferentemente a la vía LFA-1/ICAM-1, mientras que la interacción CD28/B7-1 es el inductor más eficaz de IL-2 y apoya la proliferación de células T por largos periodos de tiempo a través inducir la expresión de los factores nucleares AP-1, NF -kB, CD28RC y NF-AT. La interacción entre CD40L y CD40 proporciona una señal potente que regula la expresión de moléculas co-estimuladoras en las células presentadoras de antígenos (CPA) e induce la producción de la citoquina IL-12. En adición, la expresión de los tres miembros de la familia MAP quinasa (JNK-1, ERK-2 y p38) también requieren la presencia co-estimuladora de la vía CD28/B7-1 como una segunda señal para una óptima
CORRESPONDENCIA
ABSTRACTT-cell activation is critical for the coordination of specific immune responses against invading pathogens. Initiation of these T-cells responses requires costimulation through the T cells receptor (TCR) and costimulatory molecules expressed on T cells. The participation of these second signals are crucial, since activation of T cells by TCR in the absence of signal 2 induces anergy. Despite the actual number of molecules known, four main receptor/ligand pairs have been extensively studied and have been demonstrated to be of major importance in costimulation of T cells: CD2 / LFA-3, LFA-1/ICAM-1, CD28/B7-1/2, CD40L/CD40. These pathways seem to induce distinct effector functions in T cells subsets and thereby shape the profile of the immune response. The CD2/LFA-3 pathway seems to play a central role for expansion of naive T helper cells and is characterized by a strong adhesive function and production of TNF-α and IFN-g but is a poor inducer of IL-2. Memory cells seem to preferentially respond to LFA-1/ICAM-1 pathway, while CD28/B7-1 is the most efficient inducer of IL-2 and supports long-lasting T cell proliferation, by inducing the expression of AP-1, NF-kB, CD28RC and NF-AT nuclear factors. The CD40L-CD40 interaction delivers a potent signal that up regulates costimulatory molecules on the APC inducing the production of the cytokine IL-12. In addition, all three members of the MAP kinase family (JNK-1, ERK-2 and p38) also require the constimulatory presence of CD28/B7-1 as a second signal for an optimal activation. Interfamily redundancy of receptors/ligands offers an opportunity to regulate distinct T cell response profiles in various micro environments at separate time points of the immune response.Keywords: T-cells, T cells receptor, immune response.
INTRODUCTION
T lymphocyte activation and interleukin-2 (IL-2) production
require at least two signals, generated by the interaction
of antigen/MHC complexes with the T-cell receptor (TCR)
(signal 1) and costimulation provided by the antigen-
presenting cell (APC) through the CD28 receptor on the T
cells (signal 2) (1, 2). The participation of signal 2 is crucial,
since activation of T cells by signal 1 in the absence of signal
2 induces anergy (functional inactivation) (3, 4). All helper T
lymphocytes (CD4+) and most cytotoxic T lymphocytes
(CD8+) express the cell surface molecules CD28, CD2,
activación. La redundancia intrafamiliar de receptores/ligandos ofrece una oportunidad para regular distintos perfiles de respuesta de las células T en distintos micro-ambientes y en distintos tiempos de la respuesta inmune.Palabras Clave: Células T, receptor de las células T, respuesta inmune.
Rev. cienc. salud med. Volumen 3, Número 2, Mayo de 2016.
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ARTÍCULO DE REVISIÓN
CD40L and LFA-1. Binding of these molecules to their
respective ligands transduces signals that culminate in the
induction of several nuclear factors (i.e., AP-1. CD28RC,
NF-AT and NF-kB/Rel), which are required for the activation
of the genes necessary to deliver an immune response (5,
6). Most of these nuclear factors would normally act both as
transcriptional activators and repressors, depending on the
gene and the stimuli (7). However, despite the redundancy
in activation pathways, the CD28 receptor has been to
be essential for activation of helper T lymphocytes. It is
responsible for the delivery of the signals necessary to
strongly up-regulate the transcriptional activity of the IL-2
promoter, thus allowing its translation and the production of
IL-2 (1, 5, 6). This growth factor is mainly secreted by antigen
stimulated CD4+ (activated helper T cells).
The secreted IL-2 protein binds to its IL-2 receptor (IL-2R)
on T cells, although this interaction also plays a critical role
in the normal development, differentiation, and proliferation
of a number of immune cells, including B-cells, T cells and
NK cells. The frequency of T cells responding to a nominal
antigen is generally in the range of 1/10,000 or lower, while
the response to super antigens (SAg), which are a family
of bacterial and viral proteins, stimulate about 10 % of all T
cells (5, 6) (9 - 11). Bacterial SAg bind to MHC Class II proteins (1) and subsequently interact with T cells bearing particular
TCRV families. They bind as unprocessed proteins outside
the MHC class II peptide binding grove, and induce
activation of a large number of T cells to proliferate,
release cytokines and mediate cytotoxicity (1) ( 9 - 11). Several
molecules expressed on APC have both adhesive and
costimulatory functions (12, 13). These pathways appear to
be essential for the initiation and maintenance of a T cell
response, because blocking of one or more of the adhesion
receptor-ligand interaction prevents a primary immune
response.
Four main receptor/ligand pairs have been extensively
studied and have been demonstrated to be of major
importance in costimulation of T cells: CD2 / LFA-3, LFA-
1/ICAM-1, and CD28/B7-1/2, CD40L/CD40 (1, 11). These
adhesion/activation pathways seem to induce distinct
effector functions in T cells subsets and thereby shape the
profile of the immune response.
INDUCTION OF SIGNAL ONE AND TWO
The initial phase of T cell-APC interaction culminates with
the delivery of signal one and can be divided into at least
four stages: a) initial T cell target cell adhesion; b) ligation of
the TCR by an antigen/MHC complex; c) antigen dependent
strengthening of T cell-APC adhesion; and d) integration of
TCR costimulatory mediated signals (12 - 14). The induction
of signal 2 delivered by the interaction of costimulatory
molecules on APC such as B7-1/2, LFA-3 and ICAM-
1 with their respective receptors on T cells (CD28, CD2,
and LFA-1), will eventually activate T cells to proliferation
and cytokine production. The initiation of T cell signaling
through the TCR plus CD28, CD2 or LFA-1 induces a series
of biochemical events including kinase and phosphatase
activation and recruitment of scaffold proteins. TCR ligation
triggers the tyrosine phosphorylation of immune receptor
tyrosine-based activation motifs (ITAMs) on the TCR-
associated CD3 complex by the Src family kinases, Lck
and Fyn. This leads to the recruitment and subsequent
activation of the cytoplasmic tyrosine kinases, ZAP 70 and
Syk (15, 16).
These kinases have been shown to induce tyrosine
phosphorylation of linker for activation of T cells (LAT) (17).
LAT, a 36-38 kDa palmitoylated trans membrane protein,
becomes heavily tyrosine phosphorylated after TCR
ligation and associates with a number of effector proteins
including Grb2, Grap, PLCg, Cbl, Vav and p85 subunit
of phosphoinositide 3 kinase (PI3K) (17 - 19). Simultaneous
engagement of the CD28 receptor results in Tec kinase
association (20), p62 dok phosphorylation (21), and PI3K
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association (22 - 24). Initial costimulatory events induce a series of
biochemical events such as Ras activation, phosphoinositide
production, and calcium fluxes culminating in the induction of
genes such as IL-2, IL-2 a chain, and Bcl-XL (25). Two important
downstream pathways mediating these costimulatory events
are the ERK and JNK cascades. The ERK and JNK proteins
are members of the MAPK superfamily involved in proliferative,
apoptotic, and developmental processes. The simultaneous
delivery of these signals is crucial for T cell activation since T
cells that are exposed to APC capable of presenting antigen
but deficient costimulus become anergic (3, 4) (Figure 1).
ANTIGEN PRESENTING CELL
Costimulatory signals are delivered most efficiently by
dendritic cells, less effectively by monocytes and activated
B cells, poorly by resting B cells, and marginally by resting
T cells (26). The best studied dendritic cells in tissue are
the Langerhans´ cells, which differ from those found in
lymphoid tissue in several ways (27). Firstly, they can ingest
antigen and secondly, they lack costimulatory activity.
When the skin is infected, these cells take up antigen and
Figure 1: Two signals are required for optimal activation of T cells. A) Recognition of peptide/MHC in the absence of appropriate costimulatory signals induce functionally unresponsive or anergic T cells. B) Recognition of peptide/MHC in the presence of LFA-3 costimulatory signal induces T cells to be activated to clonal expansion and production of IL-2 in a autocrine manner. C) Recognition of peptide/MHC in the presence of the B7-1
costimulatory signal, activates T cells to proliferation and IL-2 production in a paracrine manner.
Rev. cienc. salud med. Volumen 3, Número 2, Mayo de 2016.
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are triggered to migrate through the lymph to the lymphoid
organs. There they differentiate into dendritic cells that
cannot ingest antigen but gain potent costimulatory
activity. Dendritic cells in the lymphoid tissues have a high
capacity to activate immunologically naive T cells and they
constitutively express high levels of MHC class II molecules
as well as a number of various adhesion ligands (28, 29). The
lymphoid dendritic cells are non-phagocytic and do not
readily take up antigen from the extracellular milieu. It has,
however, been suggested that they may be specialized
to present diff e rent viral peptides very efficiently on their
abundant MHC molecules (Figure 2).
Figure 2: In a, APC cell presented antigenic peptides (Ag) in the groove of MHC molecules to T cells. In b, the b-chain of the TCR recognizes SEA bound to the outside of the MHC class II molecule, away from the peptide binding groove. SEA contains two MHC class II binding sites, which bind to the a and b chains on two separate
HLA-DR4 molecules. V, variable region. C, constant region.
MEMBRANE-BOUND MOLECULES
The selectins are particularly important for leukocyte
homing to specific tissues and can be expressed either
on leukocytes (L-selectin) or on vascular endothelium
(P-selectin and E-selectin). L-selectin is expressed on naïve
T cells and binds to the carbohydrate moiety of mucin-like
molecules called vascular addressing, which are expressed
on vascular endothelium (30). The interaction between
L-selectin and the vascular addressing is responsible for
the specific homing of naive T cells to lymphoid organs. The
integrins comprise a large family of molecules that mediate
adhesion between cells and of cells to the extracellular
matrix in both immune and inflammatory reactions (31).
Integrins are made up of a large a chain that has several
cation-binding sites, which are usually occupied by calcium
ions, paired non-covalently with a smaller b chain. Most
integrins expressed on leukocytes have a common b 2
chain, but different a chains.
All T cells express the integrin LFA-1 (CD11a/CD18),
whereas macrophages express both the Mac-1 (CD11b/
CD18) and the gp 150, 95 (CD11c/CD18) molecules (11, 32).
The Ig superfamily includes the Igs, TCR, the CD4 and CD8
co-receptors, the VCAM-1, CD2, LFA-3 (CD58), CD28,
CTLA-4, B7-1 (CD80), B7-2 (CD86), CD40/CD40L and the
ICAMs, 1, 2 and 3. The CD2 /LFA-3, LFA-1/ICAM-1 and
CD28/B7 receptor/ligand pairs have both adhesive and
costimulatory functions and they seem to induce distinct
effector functions in T cell subsets and there by shape
the profile of the immune response. LFA- 3 represents
one of the most broadly expressed adhesion molecules,
whilst B7 is restricted to professional APC (33, 34). The ICAM
family of proteins is distinctly expressed in various tissues;
ICAM-1 is inducible on a wide variety of cells (11), ICAM-
2 is associated with endothelial cells (35), and ICAM-3 is
expressed constitutively on leucocytes (36). B7-1 and B7-2
are costimulatory molecules, which are mainly expressed
on professional APCs (37). CD28 is the only ligand for B7
on naive T cells, whereas activated T cells also express
the B7 ligand CTLA-4. It have been demonstrate that
CTLA-4 functions as a down regulatory molecule for T cells
when ligated to B7 (38, 39). Thus the regulation of an immune
response by costimulatory signals is governed by the tissue
distribution of various adhesion molecule ligands as well as
by the ability of these to transduce distinct signals into the
responding T cell subsets (Fig. 3).
Rev. cienc. salud med. Volumen 3, Número 2, Mayo de 2016.
THE HALLMARK OF CD28, CD2, CD40L AND LFA.1 COSTIMULATORY MOLECULES IN THE MODULATION OF T LYMPHOCYTE RESPONSE
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Figure 3: Some receptor/ligand pairs expressed by T and APC cells, with stimulatory/costimulatory activities. CD28/B7, CD2/LFA-3, LFA-1/ICAM-1, and CD40L/CD40 are the major adhesion/activation pathways for T cell activation. The growth factor IL-2 is produced by activated T lymphocytes in an autocrine and paracrine manner.
CD2/LFA-3 THE MOST IMPORTANT ADHESION PATHWAY OF RESTING T CELLS
CD2 is expressed on all T cells and interacts with LFA-3
(CD58), CD59 and CD48 ligands (40, 41). A role for CD48
has so far been only demonstrated in the murine system,
whereas LFA-3 seems to be the major ligand for CD2 in the
human. The LFA-3 binding site on CD2 has been localized
to the adhesion domain of CD2, which is the amino-terminal
domain 1 (42, 43). It is clear that the CD2/LFA-3 interaction
functions to promote T cell activation and T cell adhesion
(Fig. 4 A). The CD2 molecule on resting T cells expresses
two different epitopes, which have been identified by several
monoclonal antibodies (mAbs) including T11.1 and T11.2 (44, 45). Adhesion to LFA-3 transfected cells has been shown
to be similar by CD45RA+ naive and CD45RO+memory T
helper cells. However, the naïve T cells proliferated more
vigorously compare d to the memory T cells when activated
by SAg and HLA - DR/LFA-3 transfected cells. This
suggests that naive T cells utilize the CD2/LFA-3 pathway
for signal transduction more efficiently than memory cells.
The favorable costimulation of naïve T cells by LFA-3
expressing APC may allow rapid cell expansion during an
early phase of an immune response. A recent study has
demonstrated that mAbs directed at either the adhesion
domain of CD2 or LFA-3 specifically inhibit IL-12-induced
proliferation and IFN-g production by activated T cells
(46). Furthermore, by using activating pairs of CD2 mAb,
CD2 stimulation strongly synergized with IL-12 in inducing
proliferation and IFN-g production.
These data suggest that CD2 is a critical functional link
between T cells and APC by mediating an IL-12/IFN-g
positive feedback loop (46). Moreover, mice lacking the
functional CD2 gene generate specific CTL responses
in vivo, with no CD2 requirement for the maintenance
or activation of memory CTL (47). Taken together, the
adhesive properties of LFA-3 (Fig. 4 A), the potent effect
on proliferation of naive T helper cells (Fig. 4 B, C) and the
ability to induce strong IFN-g production in memory cells,
suggest that LFA-3 may play a central role during the early
immune response of both naive and memory T helper cells
(11). The release of IFN-g would result in up-regulation of
ICAM-1 and B7 and thereby indirectly facilitate amplification
of a secondary immune response.
Figure 4. A) LFA-3 is the major adhesion molecule for resting CD4 + T cells. The adhesion of resting CD4 T cells to untransfected CHO cells and HLA-DR transfected CHO cells co-expressing the adhe-sion molecule B7-1, ICAM-1, L FA-3 and B7-1/LFA-3, was analyzed in a cell adhesion assay of Cr uptake by the labelled T cells. Prolifer-ation of purified naive CD4 CD45RA. B) and memory CD4 CD45R0. C) T cells subsets (0.5x10 /ml) after 3 days of incubation with irra-diated CHO-DR4, CHO-DR4/B7, CHO-DR 4/LFA-3, and CHO-DR4/B7/LFA-3 (1:10 ratio to T cells) in the presence of various doses of SEA. Cultures were pulsed with [36+H] TdR on day 3 and harvested
6 h later.
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LFA-1/ICAM-1, THE MOST VERSATILE AND DYNAMIC PATHWAY
The integrin are a large family of versatile cell surface
heterodimers expressed on resting lymphocytes in a
low-avidity state. LFA-1 is the best characterized integrin
expressed by T cells and is composed of a heterodimer of
the CD11a and CD18 molecules (13, 48). The gross structure
of the first described LFA-1 ligand, ICAM-1, was initially
examined by electron microscopy and showed that the
molecule consisted of five Ig-like domains oriented ”head-
to-tail” (49). ICAM-2 contains two Ig-like domains having 36%
amino acid identity with the first two domains (D1 and D2) of
ICAM-1 (50). Cloning of ICAM-3 demonstrated the existence
of five Ig-like domains that are highly homologous to the
corresponding domains in ICAM-1 and ICAM-2 (51). ICAM-
1 can be induced on a wide variety of cells in response to
inflammatory mediators such as IFN-g, IL-1 and TNF (52).
ICAM-1 seems to be able to regulate cell trafficking during
inflammatory responses and facilitate T cell recognition of
specific antigens (53). ICAM-2 is the major ligand for LFA-
1 on resting endothelial cells, and it has been assumed
that ICAM-2 has important effects on normal recirculation
of lymphocytes (54). ICAM-3 is strongly expressed on
APCs and resting T cells (55). LFA-1 is transiently induced
to a high avidity state by ligation of the TCR or CD2 (56).
Memory T helper cells strongly bind to ICAM-1 expressing
cells in an antigen- independent manner, while naive T
helper cells fail to adhere. Upon pre-treatment with the
mAb NKI-L16, a dramatic increase in adhesion of naive
cells is seen, comparable to that of memory T cells (Fig.
5). Naive and memory T helper cells are characterized by
low and high surface levels of LFA-1, respectively (57) (Fig.
5). NKI-L16-activated naive T cells display an increased
binding without any change in the total number of LFA – 1
molecule expressed, and this argues for changes in LFA-
1 conformation rather than an altered surface level. This
suggests that memory cells express a substantial number
of activated LFA-1 molecules, whilst naive cells express
mainly the inactive form. The inactive form may play a
physiological role in keeping naive cells in the resting state,
thus avoiding irrelevant antigen triggering. Therefore, the
L FA-1/ICAM-1 pathway seems to have a unique dynamic
function in the regulation of T cell adhesion during distinct
differentiation stages.
Figure 5: The NKI-L16 mAb has the ability to increase the adhe-sion of the LFA-1/ICAM-1 pathway in both CD4+45RA+ naive and CD4+45RO memory T cells. Naive A) and memory B) T cells were pre incubated with NKI-L16 mAb for 15 min at 37ºC, before being
added to the transfected CHO cells.
CD28 IS THE PRIMARY CO-STIMULATORY SIGNAL RECEPTOR FOR T CELLS ACTIVATION, PROLIFERATION AND IL-2 PRODUCTION.
The first indication that the CD28 receptor acts as a
costimulatory T cell receptor was the demonstration that
mAb 9.3 (anti-CD28 mAb) combined with phytohemaglutinin
or PMA induced a marked increase of cell growth in human
T cells (57).
The CD28 receptor is a potent costimulators of T cells,
inducing IL-2 production, IL-2 receptor expression and
clonal expansion of T cells (Fig. 6 A). No detectable effect
on resting T cells after stimulation with anti-CD28 mAb
alone can be demonstrated (58). In addition, CD28 activation
induces production of survival factors. This is also true for
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CD152, as expression of the anti-apoptotic gene BclxL is
induced by CD152 ligation at similar levels as by CD28 (59).
The common belief is that CD152 is a negative modulator
of T cell activation, yet Liu et al. claim that CD152 is in
fact a positive costimulator y receptor (60). They have used
tumors expressing wild type and mutant CD80 to address
the role of CD152 in anti-tumor immune responses. The
expression of mutant CD80 that binds to CD152 but not
CD28 on tumor increases their immunogenicity while
reducing their tumorigenicity. In contrast, a mutant that
binds neither CD28 nor CD152 on the same tumor fails to
elicit the same effect. The two major B7 family members,
B7-1 (CD80) and B7-2 (CD86) are only distantly related
based on the amino acid sequence which shows 26%
identity (61). B7-2 is constitutively expressed at low levels
on DCs, resting monocytes and B cells. A variety of factors
regulate B7 expression, including MHC class II ligation,
cross-linking of B cell Ig receptors, CD40 ligation, mitogens
and cytokines such as IL-4 and IFN-g (62). Upon activation,
B7-2 is rapidly up regulated on DCs, monocytes and B cells (63, 64). B7-1, which shows low-level constitutive expression,
is up regulated in response to activation more slowly and to
a lower extent than B7-2 on DCs, monocytes and B cells.
Figure 6: LFA-3 and B7-1 cooperate to induce long lasting T cell proliferation. A) CD4 T cells were activated with SEA and CHO cells expressing HLA-DR4, HLADR4/LFA-3, HLA-DR4/B7, and HLA-DR4/B7-1/LFA-3. Cell proliferation was analyzed at day 3. B) CD4+ T cells were activated with SEA (10 ng/ml) and APC as indicated in
A. Cell proliferation was analyzed at days 3, 5, 7, and 10.
Overlapping and distinct functions of B7-1 and B7-2
costimulatory molecules have been proposed (65, 66).
Transfectants expressing B7-1 or B7-2 were shown to
provide similar costimulatory signals for T cell expansion,
cytokine production and generation of cytotoxic T cells
as determined by the magnitude and kinetics of the
response (66). In another study with mAbs and transfectants
expressing B7-1 or B7-2 it was demonstrated that B7-2
induced higher levels of the Th2 cytokine IL-4 than
that induced by B7-2 (67). They suggested that B7s can
differently influence the Th1/Th2 cytokine profile and that
B7-2 may be more important for the humoral response
than B7-1. It has been hypothesized that B7-2 is more
important in the initiation of T cell activation, whereas
B7-1 is more important for amplification and prolongation
of the immune response (68, 69).In experimental allergic
encephalomyelitis (EAE) (a model for multiple sclerosis
in the mouse) the effect of CTLA-4-Ig and blocking mAbs
towards B7-1 and B7-2 were demonstrated to differently
affect disease (67, 70). Treatment with blocking anti-B7-1
mAb reduced the incidence of disease, while treatment
with blocking anti-B7-2 mAbs enhanced disease severity.
This supported the idea that inflammatory cytokines play a
role in the pathogenesis of the disease. Moreover, detailed
analyses have suggested that the binding affinity of B7-1
for its receptor is somewhat higher than B7-2, whilst B7-2
appears to have a slower dissociation rate than B7-1 (71).
This implies subtle differences in binding characteristics of
the B7 family members (72). Another study confirmed these
data by showing that B7-1 and B7-2 are not equivalent in
the way that repetitive costimulation of CD4+ naive T cells
with B7-2 resulted in production of both IL-2 and IL-4. On
the contrary, the same activation with B7-1 gave high levels
of IL-2 but only low levels of IL-4 (73, 74). In our model, CHO
transfectants expressing either B7-1 or B7-2 were efficient
costimulators for T cell proliferation, cytokine production,
and generation of CTL (1, 74, 75). In addition, B7 and LFA-3
costimulation supported proliferation of T cells stimulated
with nanomolar concentration of the SAg SEA (Fig. 6 A).
Rev. cienc. salud med. Volumen 3, Número 2, Mayo de 2016.
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ARTÍCULO DE REVISIÓN
Exposing T helper cells to B7 costimulation resulted in
long-lasting proliferation (Fig. 6 B) and release of high
amount of IL-2. B7 costimulation of naive and memory T
helper cells resulted in high of IL-2 and TNF-a secretion in
both subsets, but only memory cells were able to produce
high amounts of IFN-g (Figure 7).
Figure 7: Differences in IL-2, IFN-g and TNF-b production between CD4+ 45RA (naive) and CD4+45RO (memory) T cell subsets. IL-2 production was measured from the supernatant of freshly purified naive (A, C, E) and memory (B, D,F) helper T cells (0.5 x 106/ml) cultured for 24 and 48 h with the indicated number of irradiated CHO
transfectants (0.5 x 106/ml).
However, analyzing the role of B7-1 and B7-2 costimulation
on IL-2 transcriptional activity, we found that B7-1
costimulation induced 2 times as high IL-2 transcriptional
activity and IL-2 production as CD86 (75). A further dissection
of IL-2 gene transcription demonstrated that B7-1 more
strongly induced NF-kB, AP-1 and CD28RE transcriptional
activity compared with B7-2 (77). Thus, higher levels of
transcriptional activity induced by B7-1 than B7-2 may
explain the higher induction of IL-2 protein induced by B7-1
compared with B7-2.
THE EFFECTS OF COSTIMULATORY SIGNALS ON THE ACTIVITY OF AP-1, NF-AT, NF-kB AND CD28RC TRANSCRIPTION FACTORS
Production of IL-2 is considered to reflect a checkpoint in
commitment to T cell expansion. The regulation of the IL-2
enhancer/promoter region has been studied intensively
as a key target for control of T cell growth. The minimal
inducible IL-2 enhancer region has been identified as
a region located within 300 bp from 5’-end of the IL-2
transcription start site (7, 28, 76). Located within this region is
a number of target DNA-motifs for ubiquitous as well as
T-cell specific transcriptional factors. These include binding
sites for AP-1, the octamer- binding (Oct) protein 1 and
2, nuclear factor of activated T cells (NF-AT), the NF-
kB, and the CD28-responsive complex (CD28RC) (7, 28,
76). The simultaneous presence of these trans activating
factors is required to obtain optimal activation of IL-2 gene
transcription and emphasizes the role of these transcription
factors as a point of signal integration.
Among the transcription factors binding to the IL-2 enhancer,
AP-1 and NF-kB appear to be of central importance for
the immune response. They are involved in the induction
of several different cytokine gene promoters and also
participate as partners in combinatorial interactions between
the NFAT, Oct, and CD28RC-transactivating function (77, 78).
The AP-1 family of transcription factors include Jun, Fos,
ATF-2, and their relatives. This family induces transcription
of numerous genes through tumor promoting agent (TPA)
response elements (TREs) and cAMP response elements
(CREs). Structurally, AP-1 members contain a basic region
leucine zipper (bZIP) motif mediating both dimerization
among family members and DNA binding.
Transcriptional activity of c-Jun and ATF-2 is mediated by
JNK phosphorylation on serine/threonine residues at their
transcriptional activation domains. The NF-AT family of
transcription factors contains a conserved domain distantly
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THE HALLMARK OF CD28, CD2, CD40L AND LFA.1 COSTIMULATORY MOLECULES IN THE MODULATION OF T LYMPHOCYTE RESPONSE
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ARTÍCULO DE REVISIÓN
related to RHD. NF-AT activity is induced by calcium
signals. Calcium influxes activate the calcium/calmodulin
regulated serine/threonine phosphatase calcineurin, which
dephosphorylates NF-AT and contribute to its nuclear
translocation (79, 80). The kB-DNA motif is recognized by
proteins of the NF-kB/Rel family of transcription factors.
The cRel/ NF-kB transcription factors and IkB proteins are
an evolutionarily conserved family which modulates gene
induction during immune, inflammatory, and acute phase
responses.
The cRel/ NF-kB transcription factors include cRel, p65,
p50, p52 and Rel B, which contain an amino-terminal
Rel-homology domain (RHD). This conserved, 300
amino acid domain contains subdomains mediating DNA
binding, dimerization, nuclear localization, and IkB protein
interactions. Responses to stimuli such as TNFa, IL-1, UV
light, and T-cell costimulation cause IkB phosphorylation,
ubiquitination and proteasome-mediated degradation (81, 82).
In our system, gel shift analysis revealed that stimulation
with antigen alone induced NF-kB binding whereas
induction of AP-1 binding proteins required costimulation.
LFA-3 induces moderate levels of AP-1 and does not
influence levels of NF-kB. Stimulation with B7-1 induces
strongly AP-1 and enhances NF-kB binding (5, 6). Supershift
analysis of the NF-kB complex revealed the presence of
p50, p65, and small amounts of c-Rel proteins while the
AP-1 binding complex contained c-Jun, Jun-D and Fra-1.
The sum of these results suggests distinct effects of B7-1
and LFA-3 costimulation on the activity of AP-1 and NF-kB.
These may partly account for the differential effects of B7-1
and LFA-3 costimulation on IL-2 expression. Luciferase
reporter constructs containing the IL-2 promoter region
(-500 to +60) and multimers of NF-AT, NF-kB, AP- 1 and
CD28RE, showed that DNA binding of NFAT, NF-kB, AP-
1, CD28RE and Oct-1 and transcription of the luciferase
gene driven by multimerized binding sites for these nuclear
factors are differentially induced when SAg is presented by
CHO cells transfected with B7-1 and/or LFA-3. It was shown
that CD2 and CD28 activation induced differing patterns of
NF-AT complexes and NF-AT associated proteins (6). CD28,
but not LFA-3 costimulation led to the induction of factors
binding to the CD28RE in the IL-2 promoter. Mutation of the
CD28RE in the IL-2 promoter reduced the CD28 induced
IL-2 transcription significantly (Figure 8).
Figure 8: Functional demonstration of the specificity of the CD28RE on the transcriptional activity of a wild type and a mutated version of the IL-2 promoter. Leukemia Jurkat T cells were transfected with the wild type IL-2 luciferase reporter gene or with the mutant version. Af-ter 24 h incubation the cells were stimulated with SEE and the CHO-DR, CHO-DR/LFA-3, and CHO-DR/B7-1 transfectants. Eight hours later, samples were harvested and analyzed for luciferase activity. The native CD28RE sequence of the IL-2 promoter 5´-AAATTC-3´ was mutated to 5´-CCTCGA-3´. Luciferase activity is expressed as
arbitrary light units minus background units of buffer alone.
In general, CD28/B7 interaction led to a greater induction of
the IL-2 promoter activity, NF-kB and AP-1 expression. The
combination of overexpression of p65 and c-Jun was very
effective in activating the IL-2 promoter and was dependent
on the CD28RE (83). Overexpression of p65 and c-Jun was
able to hyper induce LFA-3 expression and synergize with
signal 1 to induce similar levels of transcriptional activity to
that observed by the wild type IL-2 promoter after HLA-DR/
B7-1 costimulation.
This led us to propose that transition of IL-2 expression
from an LFA-3 autocrine response to a B7-1 paracrine
response involves the activation of p65 and c-Jun and the
CD28RE in the IL-2 promoter effecting diverse cellular
Rev. cienc. salud med. Volumen 3, Número 2, Mayo de 2016.
PARRA E. ET AL.
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ARTÍCULO DE REVISIÓN
programs such as activation, proliferation, differentiation,
and apoptosis (84, 85). B7-1 costimulation induced strong
activation of all three MAPK members (JNK-1, ERK-
2 and p38), compared with the CD2/LFA-3 pathway that
induce ERK-2 expression but only moderately p38 (Fig. 9).
Contrary to what has been previously proposed, we show
that SEE (signal 1)-induced activation of the ERK pathway
is further increased by costimulation with either B7-1 or
LFA-3. These observations suggest that the integration of
signals that lead to T cell activation and IL-2 induction may
occur in the JNK pathway. It is tempting to suggest that
the differential signaling between CD28 and CD2 in these
events may be explained by the differential effect on the
MAPK observed in our results (Figure 9).
Figure 9: Activation of the JNK-1 (A), ERK-2 (B) and p38 (C) MAPKs by SEE (100 ng/ml) and the CHO-DR, CHO-DR/B7-1 and CHO-DR/LFA-3. Jurkat cells were incubated in medium containing 10% FBS. The cells were stimulated with and without SEE and the various CHO transfectants for the indicated periods of time. Whole cell ex-tracts were pre p a red and assayed using and immune complex kinase assay with GST-c-Jun, MBP, and GSTATF-2 as substrates for JNK, ERK2, and p38, respectively. The cpm activity with respect
to untreated cells is shown.
CONCLUDING REMARKS
During the last decade, the number of members of the
adhesion molecule family has continued to increase. Until
the middle of 90s, the only known ligands to the CD2 and
LFA-1 receptors were LFA -3 and ICAM-1, respectively.
CD48 and CD59 have thereafter been found to serve as
supplementary ligands for CD2 and ICAM-2/ICAM-3 for
LFA - 1.
Moreover, when the receptor-ligand pairs CD28/B7-1 and
CTLA-4/B7-1 were first described, it was anticipated that
other ligands might exist; these have now been identified as
B7-2. At least two different ligands to each receptor seem
to exist within these families of adhesive and costimulatory
molecules. Most likely, the immune system has evolved this
redundancy to fine-tune the immune response.
The need for T cell costimulation has been shown to be
extremely important in the generation of potent T cell
responses, especially when the antigen in question is
weakly immunogenic. It has now been demonstrated that
T cells actually acquire T cell costimulatory molecules from
APC upon activation. Depending on the level of signal 1
and the level of expression of costimulatory molecules,
this phenomenon can have either immune stimulatory or
immune regulatory consequences.
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Etapa 2 En la segunda etapa se debía confeccionar la portada de la revista, para ello se debía tomar una fotografía propia y editarla. Este numero al contar con mas artículos de radiología, se confeccionó una portada acorde a un tema radiológico.
A continuación portada de la revista.
Etapa 3Realizar distintas propuestas de afiches publicitarios insertos en la revista. Estos afiches si bien son de eventos o instituciones prestigiosas no contaban con su propio afiche o en algunos casos una buena publicidad. Estos afiches solo estarán dentro de la revista como anexos.
A continuación 2 publicidades.
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Ponemos a disposición de toda la comunidad científica los artículos correspondientes al número de Mayo, publicados en la Revista de Ciencias de la Salud y Medicina.
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Etapa 4En esta etapa se debían adaptar los distintos artículos de los 3 números de la revista a una versión Html, en la pagina web: “www.rcienciasdelasaludymedicina.cl”, que aun se encuentra en proceso de actualización.
A continuación se presentan las siguientes capturas del sitio web:www.rcienciasdelasaludymedicina.cl/new
Etapa 5Se debían realizar posibles propuestas de diseño para una aplicación movil, donde el cliente podría leer la revista de manera sencilla, lograr una mayor accesibilidad y popularidad entre los interesados.
A continuación se presentan la propuesta.
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Articulos en HTML
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Diseño para aplicación móvil
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PRÁCTICA PROFESIONALPRODUCCIÓN EDITORIAL
P. Profesional. Sofía Bustamante Leguia, Universidad de Tarapacá.
REVISTA DE CIENCIAS DE LA SALUD Y MEDICINA
ReCISAM
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