Transcript T cell-mediated immune response

Defense against pathogens,
tumour immunology,
transplantology
Martin Liška
Extracellular microorganisms
• Typically bacteria or parasites
• For defense against extracellular microbes
and their toxins, specific humoral immune
response is important
Humoral immune response
• Recognition of antigen by specific Ig, bound in
cell membrane of naive B lymphocyte
• The binding of antigen cross-links Ig receptors of
specific B cells and then biochemical signal is
delivered to the inside B cell; a breakdown
product of the complement protein C3 provides
necessary „second signal“
• Clonal expansion of B cell and secretion of low
levels of IgM
Humoral immune response
• Protein antigens activate CD4+ T helper cells
after presentation of specific antigen
• T helper cells exprime CD40L on their surface
and secrete cytokines → proliferation and
differentiation of antigen-specific B cells,
isotype switching, affinity maturation
Phases of humoral immune
response
Effector functions of antibodies
• Neutralization of microbes (incl.viruses) and
their toxins
• Opsonization of microbes (binding to Fc
receptors on phagocytes; at the same time,
stimulation of microbicidal activities of
phagocytes)
• ADCC (Antibody-dependent cell-mediated
cytotoxicity) – IgG opsonized microb is destroyed
by NK cells after its binding to IC
• Activation of the complement system (classical
pathway)
Defense against extracellular pathogens
(bacteria and unicellular parasites)
a/ non-specific (innate) immune system
- monocytes/macrophages, neutrophils,
complement system, acute phase proteins
(e.g.CRP)
b/ specific (adaptive) immune system
- antibodies (opsonization, neutralization)
Defense against multicellular
parasites
• Production of IgE → coating and
opsonization of parasites
• Activation of eosinophils - they recognize
Fc regions of the bound IgE, then they are
activated and release their granule contents
(MBP,ECP,EPO), which kill the parasites
• Th2-lymphocytes support this type of
immune response
Intracellular microorganisms
• Initially: non-specific immune response (ingestion
by phagocytes)
• Some microorganisms are able to survive inside
phagocytes (e.g. some bacteria, fungi, unicellular
parasites, viruses) – they survive inside
phagosomes or enter the cytoplasm and multiply
in this compartment
• The elimination of these microorganisms is the
main function of T cells (specific cell-mediated
response)
Processing and presentation of
antigen
• Professional antigen-presenting cells:
macrophages, dendritic cells, B lymphocytes
(they express constitutionally class II MHC)
a/ exogenous antigens – e.g. bacterial, parasitic
- hydrolysed in endosomes to linear peptides →
presentation on the cell surface together with class
II MHC to CD4+ T lymphocytes
Processing and presentation of
antigen
b/ endogenous antigens – e.g. autoantigens,
foreign antigens from i.c. parasites or
tumorous antigens
- hydrolysed to peptides → associated with
class I MHC → presentation on the cell
surface to CD8+ T lymphocytes
T cell-mediated immune response
• Presentation of peptides to naive T lymphocytes
in peripheral lymphoid organs → recognition of
antigen by naive T lymphocytes
• At the same time, T lymphocytes receive
additional signals from microbe or from innate
immune reactions → production of cytokines →
clonal expansion → differentiation → effector
& memory cells → effector cells die after
elimination of infection
T cell-mediated immune response
• TCR (T cell receptor) – T cell antigen-specific
receptor
- TCR recognizes (together with co-receptors - CD4
or CD8) the complex of antigen and MHC
- a signal is delivered into the cell through
molecules associated with TCR and co-receptors
(CD4 or CD8) after antigen recognition
T cell-mediated immune response
• APC exposed to microbes or to cytokines
produced as part of innate immune reactions to
microbes express costimulators that are
recognized by receptors on T cells and delivered
necessary „second signals“ for T cell activation
• Activated macrophages kill ingested bacteria by
reactive oxygen intermediates, NO and lysosomal
enzymes
Function of Th1and Th2
lymphocytes
Activation of T lymphocytes
Mechanisms of resistance of
intracellular microbes to cell-mediated
immune response
• Inhibiting phagolysosome fusion
• Escaping from the vesicles of phagocytes
• Inhibiting the assembly of class I MHCpeptide complexes
• Production of inhibitory cytokines
• Production of decoy cytokine receptors
Defense against intracellular
pathogens (bacteria and unicellular
parasites)
• Intracellular bacteria (Mycobacteria,
Listeria monocytogenes), fungi
(Cryptococcus neoformans), parasites
(Plasmodium falciparum, Leishmania)
• Specific immune response is necessary
Anti-viral defense
• Viruses may bind to receptors on a wide
variety of cells and are able to infect and
replicate in the cytoplasm of these cells,
which do not possess intrinsic mechanisms
for destroying the viruses
• Some viruses can integrate viral DNA into
host genome and viral proteins are produced
in the infected cells (e.g. Retroviruses)
Tumor immunology
Tumor antigens
• Mutant proteins (the products of carcinogen- or radiationinduced animal tumors)
• Products of oncogenes or mutated tumor suppressor genes
(Bcr/Abl fusion protein)
• Overexpressed or aberrantly expressed self protein (AFP
in hepatomas)
• Oncogenic virus products (HPV products in cervical CA)
Tumor immunology
Mechanisms of defense
• The principle is formation of cytotoxic T lymphocytes
clone (CTL) specific for tumor antigens
• The cooperation of naive CD8+ T cells and APC (costimulation) and T-helper cells of the same antigenic
specifity (cytokines) is required
• APC enables formation of antigen-specific CD8+ T
cells and CD8+ T cells = cross presentation
Tumor immunology
• Ig, activated macrophages and NK-cells
also participate in anti-tumor-defense
• Immunotherapy of tumors – aims to
enhance anti-tumor immunity passively (by
providing immune effectors) or actively
(vaccination with tumor antigens or with
tumor cells engineered to express costimulators and cytokines)
Tumor immunology
How tumors evade immune responses:
a/ lack of T cell recognition of tumor
- generation of antigen-loss variant of tumor cells
- mutations in MHC genes or genes needed for
antigen-processing
b/ inhibition of T cell activation
- production of immuno-suppressive proteins
Transplantation immunity –
alloimmune reaction
• Recipient’s T cells recognize donor’s allogeneic
HLA molecules that resemble foreign peptideloaded self HLA molecules
• Graft antigens are recognized:
a/ Directly – donor’s HLA molecules on graft APC
bind peptide fragments of allogeneic cellular
proteins (different from that ones that recipient’s
APC bind)→ they are recognized by recipient’s T
cells as foreign
b/ Indirectly – graft antigens are presented by
recipient’s APC to recipient’s T cells
Transplantation immunity alloimmune reaction
Antibodies against alloantigens
• They can react with HLA molecules or with
another surface polymorphic antigens
• Especially the complement binding
antibodies have harmful effect (cytotoxic)
• Possible presence of preformed antibodies
(e.g. after blood transfusion, repeated
pregnancy)
Immunologically privileged tissue
• In allogeneic transplantation, some tissues are
rejected less frequently (e.g. CNS, cornea,
gonades).
• The mechanisms of protection from the immune
system: separation from the immune system
(haematoencephalic barrier); the preference of
Th2- and suppression of Th1-reactions; active
protection from effector T cells
• The privileged status is not absolute (see MS)
Types of transplantation
• Autologous – within the same individual (e.g. a skin graft
from an individual’s thigh to his chest); that is, they are not
foreign
• Syngeneic – in genetically identical individuals (e.g.
identical twins); that is, they are not foreign
• Allogeneic (alloantigens) – in genetically dissimilar
members of the same species (e.g. a kidney transplant from
mother to daughter); it is foreign
• Xenogeneic (heterogeneic) – in different species (e.g. a
transplant of monkey kidneys to human); it is foreign
Immunological examination before
transplantation
• HLA is the most important
• MHC genes are highly polymorphic =
there is a great number of gene variants
(alleles) in the population
• MHC haplotype = a unique combination of
alleles (at multiple loci) encoding HLA
molecules, that are transmitted together on
the same chromosome
HLA typing
1/ Sera typing – identification of specific class I and
class II HLA molecules using sera typing
- less time-consuming method, however, also less
accurate
2/ DNA typing – human DNA testing by PCR
- low resolution (groups of alleles), high resolution
(single alleles)
- more time-consuming method, however, also
highly accurate
Transplantation immunity - tests
• Mixed lymphocyte reaction = T cells from one
individual are cultured with leukocytes of another
individual → the magnitude of this response is
proportional to the extent of the MHC differences
between these individuals
• Cross match = preformed antibodies detection
test (donor’s serum is mixed with recipient’s
lymphocytes in the presence of complement
proteins → if preformed cytolytic antibodies are
present in serum then the lysis of donor’s
leukocytes occurs)
Rejection
= rejection of the graft by recipient’s immune system, which considers it as non-self
• Hyperacute rejection (minutes)
– mediated by preformed antibodies (natural or generated after previous
immunization) → complement fixation → endothelial injury; activation of
haemocoagulation → thrombosis of graft vessels → accumulation neutrophils →
amplification of inflammatory reaction
• Acute rejection (days or weeks)
– mediated by T cells (→ graft cells and endothelial injury) and by antibodies (thes
bind to endothelium)
• Chronic rejection (months or years)
– mediated by alloantigen-specific T cells → cytokines, stimulating growth of vascular
endothelial and smooth muscle cells and tissue fibroblasts
Graft versus Host reaction (GvH)
= donor’s T cells, present in graft recognize
recipient’s tissue antigens as non-self and,
therefore, they react to them
1/ Acute GvH – days or weeks after transplantation
→ liver, skin and intestinal injury
2/ Chronic GvH – moths or years after
transplantation → chronic vascular, skin, organs or
glands inflammation → replacement of functional
by fibrous tissue, disorder of graft’s blood
circulation → loss of tissue function
Therapeutic approaches of GvH
prevention and treatment
• The selection of an appropriate donor
• Immunosupression – the development of
coexistence is possible later
• Donor’s T cells replacement from the graft
Maternal-foetal tolerance
• Th2-type responses in mother
• Protective effect of hormones – hCG,
estrogens
• Specific placental (Bohn’s) proteins –
immunosuppressive effect
• Blocking antibodies
• Sialomucinous membrane – between
mother and fetus
Rh incompatibility
Mother Rh-/Foetus Rh+: delivery →
senzitization (anti-D antibodies); next
pregnancy (Rh incompatibility) → anti-D IgG
pass through the placenta into foetal
circulation → destruction of foetal
erythrocytes → hemolytic anemia
Prevention: administration of anti-D to Rhmother after delivery of Rh+ child