presentación antigénica

inmunología básica,
2010

Tuesday, June 22, 2010

 Las células que exhiben péptidos asociados a moléculas MHC se denominan
células presentadoras de antígenos (APCs). Ciertas APC presentan antígenos a
linfocitos T vírgenes durante la fase de reconocimiento de respuestas inmunes
para iniciar dichas respuestas, mientras que otras APC presentan antígenos a
linfocitos T diferenciados durante la fase efectora para iniciar mecanismos que
eliminen dichos antígenos.

La mayoría de linfocitos T reconocen péptidos, no otras moléculas, porque las

moléculas MHC unen péptidos solamente.

Linfocitos T reconocen determinantes lineales, no conformacionales, porque los

péptidos se unen a las hendiduras MHC linealmente (extendidos).

Linfocitos T reconocen antígenos asociados a células, no solubles, porque las

proteínas MHC son proteínas de membrana que exhiben péptidos unidos
estabilizados en la hendidura de la molécula MHC.

Linfocitos T CD4+ y CD8+ reconocen preferentemente antígenos “muestreados” de

reservorios extracelulares y citosólicos respectivos. Porque las vías de ensamble
de moléculas MHC aseguran que las moléculas MHC Clase II exhiban péptidos
derivados de proteínas extracelulares que se han internalizado en vesículas de
APCs. Mientras que moléculas MHC Clase I presentan péptidos derivados de
proteínas citosólicas. Por otra parte, los co-receptores CD4 y CD8 se unen a
regiones no polimórficas de moléculas Clase II y Clase I, respectivamente.
Tuesday, June 22, 2010
Tuesday, June 22, 2010
 ¿EN QUE CONSISTE MHC?

MHC es una colección de genes situados en una tira

continua de DNA en el cromosoma 6 en humanos, y en
el cromosoma 17 en el ratón.

MHC constituye el Complejo HLA en humanos,

Complejo H-2 en ratones (murino)

Tuesday, June 22, 2010

 Location and Organization of the HLA Complex on Chromosome 6
Klein, J. et al. N Engl J Med 2000;343:702-709

Tuesday, June 22, 2010

Tuesday, June 22, 2010
Tuesday, June 22, 2010
 Klein, J. et al. N Engl J Med 2000;343:702-709 2.2.2.2
Tuesday, June 22, 2010
Tuesday, June 22, 2010
 La mayoría de linfos T reconocen solo péptidos, mientras que linfos B
pueden reconocer péptidos, proteínas, ácidos nucleicos, polisacáridos, lípidos, y
químicos pequeños. Como resultado, las respuestas inmunes mediadas por
linfos T están inducidas por antígenos proteicos (la fuente natural de péptidos
extraños), mientras que las respuestas inmunes humorales pueden ser debidas
a antígenos proteicos y no proteicos

Pequeñas poblaciones de linfos T son capaces de reconocer antígenos no

peptídicos; entre ellas se incluyen linfocitos NK-T y linfocitos T γδ

Linfos T son específicos para secuencias de aminoácidos en péptidos. En contraste, linfos B

pueden reconocer determinantes conformacionales que existen cuando los antígenos -como las
proteínas globulares, por ejemplo- se encuentran en configuración nativa terciaria (doblados)

◦ Al inmunizar un animalito con una proteína nativa, linfos T específicos

estimulados responderán a las formas desnaturalizadas o que han sido
digeridas por proteólisis.
◦ En contraste, luego de inmunizar con una proteína nativa, linfos B producen
anticuerpos que reaccionan solo con la proteína nativa.

Tuesday, June 22, 2010

 Los receptores antigénicos de linfos T reconocen muy pocos residuos (de
aminoácidos) de un solo péptido. Linfos T diferentes pueden distinguir péptidos
que difieren hasta en un solo residuo de aminoácido.

Linfos T reconocen y responden a péptidos antigénicos foráneos solo

cuando dichos antígenos se hallan asociados a la superficie de APCs,
mientras que linfos B y Ac secretados unen antígenos solubilizados en líquidos
corporales o bien expuestos en superficies celulares. Linfos T solo reconocen
péptidos unidos y exhibidos por moléculas MCH, y estas moléculas son
proteínas de membrana expresadas en APCs.

Linfos T de un individuo reconocen Ag’s solo cuando estos péptidos se

muestran por moléculas MHC del mismo individuo. Esta característica del
reconocimiento antigénico por linfos T se denomina restricción por MHC
propio.

Tuesday, June 22, 2010

 Vía del citosol, proteínas
endógenas

Vía endocítica, proteínas

exógenas

Klein, J. et al.
N Engl J Med 2000;343:702-709

Tuesday, June 22, 2010

 ¿y lípidos?

Tuesday, June 22, 2010

Tuesday, June 22, 2010
 Vía del citosol para
moléculas MHC
Clase I

Tuesday, June 22, 2010

 ¿y lípidos?

Tuesday, June 22, 2010

 Vía endocítica para moléculas
MHC Clase II

Tuesday, June 22, 2010

 moléculas MHC no clásicas

Tuesday, June 22, 2010

 MHC clásico: moléculas Clase I

Tuesday, June 22, 2010

 MHC clásico: moléculas Clase II

Tuesday, June 22, 2010

 Casi toda célula nucleada exhibe
MHC Clase I. Es “libro abierto”
para linfocitos T-CD8+

MHC Clase II sólo se exhibe en

APCs, para linfocitos T-CD4+

Tuesday, June 22, 2010

Tuesday, June 22, 2010
 Interactions between HLA Molecules and Peptides Interactions between a T-Cell Receptor and the HLA-Peptide Complex

Tuesday, June 22, 2010

Tuesday, June 22, 2010
 Does our current understanding of the molecular basis of immune tolerance
predict new therapies for autoimmune disease?
Nat Clin Pract Rheumatol (2006) 2:491-499

W
DEC205= dendritic cell receptor for endocytosis
/clinicalpractice/rheum
(lymphocyte Ag 75 or CD205)
Lysosomal processing

MHC
class II
DC

TCR Naive T cell

Specific
antigen
DEC205

TREG

Initial expansion
Apoptosis
Figure 1 Modification of dendritic cells by targeted antigen presentation leads to induction of T-cell
Tuesday, June 22, 2010
 ¿y qué con lípidos?

Tuesday, June 22, 2010

 nate interactions with their TCR27,28. Together, these
studies indicate that microbial-induced stimulation of
CD1d-restricted T cells is a mechanism of protection
during infection.
Self lipids. Endogenous lipids, including glycolipids
and phosphoglycerolipids, represent another important
saturated or monounsaturated long-chain fatty acid.
Both the type of base and the structure of the fatty acid
determine the membrane distribution of the glycolipids
inside the cell, their association with other molecules,
the rate of degradation and their persistence in the
cell29. All of these features are relevant for immune
recognition. Another important aspect is that differ-

Recognition of lipid antigens by T cells

source of stimulatory antigens. Glycolipids are minor
constituents of biological membranes, and are mostly
composed of a hydrophobic ceramide and a hydrophilic
ent cell types and tissues synthesize and accumulate
glycosphingolipids with modified ceramide structures.
A classical example is sulphatide, which is synthesized
Nat Rev Immunol (2005), 5:485-496
oligosaccharide chain. Ceramides are amides of fatty with different acyl chains in the brain (mainly in the

NH OH
OH Phosphatidylinositolmannoside
O O
HO
HO
NH O O– O
O
O P
HO
HO O O
O
Didehydroxymycobactin HO
O O
O
HO
O HO O
O
OH
HN OH
O NH
CH3
N O
O OH Diacylsulphoglycolipid
HO O O
HO
OH
HO3S O
O
OH
O O

OH O OH
HO OH
O Mannosyl-β1-phosphomycoketide O α-Galacturonosylceramide
OH O
HO
HO OH O O O
P HN
–O O OH O
HO

OH

Mycolic acid OCH3

HO
–O

OH
Glucose monomycolate
HO O O
HO
O O
HO
HO
O

Figure 1 | Structures of representative bacterial antigenic lipids. Most of the identified antigenic lipids are localized
in the cell walls and membranes of mycobacteria, although other bacteria also produce antigenic lipids; for example,
α-galacturonosylceramide is produced by Sphingomonas species. Antigenic lipids have heterogeneous acyl appendages in
terms of their number, length and structure. Also, the hydrophilic moiety is highly variable and might include short structures,
such as the -OH and -COOH groups in mycolic acid, complex sugars, such as those in lipoarabinomannan and phosphatid-
Tuesday, June 22, 2010 ylinositolmannoside, or short peptides, such as those in didehydroxymycobactin.
 Recognition of lipid antigens by T cells
Nat Rev Immunol (2005), 5:485-496
REVIEWS

HO OH
HO OH

OH OH H2N O
OH OH O OH
O O HO HO
O OH O COOH HO O

OH O HNAc
HO Ganglioside GM1 OH
OH

O O
OH OH
O O Isoglobotrihexosylceramide
OH OH
HO O OH HO O OH

HO HO
O O
HN HN
Phosphatidylinositol
O O– O O
OH P Sulphatide
O
HO
O O O OH OH
HO
HO O –O S
OH 3 O HN
O
O OH

HO OH OH
O
Mannosyl-β1-phosphodolichol

HO OH O O
P
–
O O

14
Figure 2 | Structures of representative self-antigenic lipids. Ganglioside GM1, phosphatidylinositol and sulphatide are
present in cell membranes and are abundant in myelin. Although isoglobotrihexosylceramide has not yet been biochemically
Tuesday, June 22, 2010 identified in human and mouse cells, it might be an endogenous ligand of invariant natural killer T cells. Self-antigenic lipids are
 Mechanisms of lipid-antigen generation and presentation to T cells.
TRENDS in Immunology (2006), 27:485-492
Review TRENDS in Immunology Vol.27 No.10

les traffic in different endosomal compartments. CD1a recycles through early endosomes (EE) and does not reach mor
and CD1c internalize in late endosomes (LE) and lysosomes (Ly) where they localize in the limiting membrane and in the me
throughout EEs and LE–Ly compartments. Lipid-internalizing receptors, such as LDL receptor, CD91 and mannose receptor fa
Tuesday, June 22, 2010
 A complex antigen that requires the partial degrada- are selectively
tion of the sugar moiety is LAM, which is loaded into for antigen pr
CD1b molecules in late endosomes44. However, the potentially in
Recognition of lipid antigens by T cells
enzymes that are involved in LAM degradation are,
again, unknown. The processing of the lipid moiety of
ized in late, b
facilitates the
Nat Rev Immunol (2005), 5:485-496
immunogenic glycolipids has not been reported. In the case o
essed molecu
somes throug
LAM/PIM then internal
M. tuberculosis late, but not e
LIPIDTRANSFER
Putative receptors
loading (see b
somes induce
molecules44 an
Plasma
membrane
that are prese
Mannose lipid-antigen
CR3 receptor
DC-SIGN
LDL-R CD36 complete unfo
family CD14 and open F′ a

Lipid traffick
the immunog
Mannosidases (?)
Hydroxylases tribution on
molecules dis
distribution a
ous movemen
Lipases (?)
Neutral and a
Uptake of Glycolipid tralized by pr
mycobacteria processing By contrast, th
most lipids w
Phagosome Late endosome
of the immun
Figure 3 | Lipid uptake and processing. The internalization of Mycobacterium tuberculosis mechanisms t
Tuesday, June 22, 2010
 Recognition of lipid antigens by T cells
Nat Rev Immunol (2005), 5:485-496 REVIEWS
REVIEWS

β2m b c
a β2m b c
D1a CD1b CD1c
CD1a CD1b CD1c
lasma
membrane Plasma
membrane

ARF6
ARF6
Clathrin Clathrin AP2 AP2
coated pit coated pit ? ?

TGN TGN
Early Early
R ER endosome
Lysosome Lysosome
Early endosome endosome
Early endosome MIIC
MIIC
ER ER AP3 AP3
Golgi Golgi
Late endosome Late endosome

d d e e
CD1d
CD1d

Late
Late endosome
endosome

AP3 CD1e
| Intracellular trafficking of CD1 molecules. Newly synthesized CD1 molecules are transported through the Golgi
Figure 4AP3
CD1e
and trans-Golgi network (TGN) to reach the cell surface, with the exception of CD1e, which remains in the cell. Cell surface CD1
Figure 4 | Intracellular trafficking
molecules of CD1inmolecules.
are internalized Newly
clathrin-coated pits synthesized
and are sortedCD1 molecules
as follows. are transported
a | CD1a through
routes to early theendosomes
recycling Golgi and
and trans-Golgi network (TGN) to reach the cell surface, with the exception of CD1e, which remains in the cell. Cell
back to the plasma membrane in an ADP-ribosylation factor 6 (ARF6)-dependent manner. b | CD1b, after interacting with surface CD1
Tuesday, June 22, 2010 molecules are internalized in clathrin-coated
adaptor protein pits and are
2 (AP2), is transported to sorted
the late as follows. aand,
endosomes | CD1a
afterroutes
bindingtotoearly
AP3,recycling
traffics toendosomes
the lysosomes.andc | CD1c, after
 Recognition of lipid antigens by T cells
Nat Rev Immunol (2005), 5:485-496

cathepsin
maturati
the thym
by inhibi
reduce th
Plasma membrane when the
With
Golgi
TGN
Late endosome/MIIC question
promote
d
ER repertoir
Lipid organs? I
antigen
resembli
MTP c Is TCR tr
Microorganism
CD4 and
a
b Priming,
LTP priming o
periphera
CD1 β2m
peptide-s
Figure 5 | Lipid loading on CD1 molecules. a | In the endoplasmic reticulum (ER), CD1d lipid that prim
loading is assisted by the microsomal triglyceride-transfer protein (MTP). MTP facilitates the
Tuesday, June 22, 2010 express a
 The who, how and where of antigen presentation to B cells
WS Nat Rev Immunol 2009; 9:15-27

a Lymph node Spleen

Afferent lymph
Red pulp
Trabecular
sinus Paracortex White
Subcapsular pulp
sinus

Follicle

HEV Marginal
zone
Medulla
Marginal
Efferent
sinus
lymph
PALS
Blood Central
Conduit network arteriole
Conduit
network
Follicle
Arteriole
branch

b Conduit network c SCS Follicle T-cell zone

Tuesday, June 22, 2010

 The who, how and where of antigen presentation to B cells
Nat Rev Immunol 2009; 9:15-27

a
Afferent lymph vessel

Antigen
C3 fragment
Antibody Subcapsular sinus
Immune
MAC1 complex
DC-SIGN

FcR SCS macrophage

BCR Small soluble

antigen
CR

Antigen-specific Follicular
B cell dendritic cell

Primary follicle

b c
SCS Antigen-specific Paracortex
B cell
HEV

Recently
Tuesday, June 22, 2010
migrated DC
 próximas:

complejo mayor de histocompatibilidad

citotoxicidad mediada por células

Tuesday, June 22, 2010