immunology - ruhr-universität bochum · antigen peptide: mhc-class-i on infected cell peptide:...
TRANSCRIPT
The role of T-effector cells in the immune response against
microbes
cellular immunity humoral immunity
Pathogens Vacciniavirus,
Influenza virus, Rabies virus
Mycobacterium tuberculosis,
Mycobacterium leprae,
Clostridium tetani, Staphylococcus aureus,
Streptococcus pneumoniae
localization Cytosol Phagosomes of macrophages
Extracellular
T-lymphocytes Cytotoxic CD8+ T-lymphocyte
TH1 CD4+ T-lymphocyte
TH2 CD4+
T-lymphocyte
Recognized
antigen
Peptide: MHC-class-I on
infected cell
Peptide: MHC-class-II on infected
macrophages
Peptide: MHC-class-II on antigen specific B-
lymphocytes
Effector
mechanism
Killing of infected cells
Activation of macrophages
Induction of antibody production of B-cells
Activated Lymphocyte in blood
All T-lymphocytes are derived from
hematopoethic stem cells from the
bone marrow
Life cycle of T-lymphocytes
Development of T-lymphocytes in the thymus
Figure 7-21 part 1 of 3
Rearrangement of TCR genes in the genome I
Figure 7-21 part 2 of 3
Rearrangement of TCR genes in the genome II
Rearrangement of genes in the genome III
b-chain a-chain
V-segments 52 70
D-segments 2 0
J-segments 13 61
N- and P-nucleotids 2 1
Number of theoritical rearrangements 1352 4270
Combinatorial diversity 5,7 x 106
Total diversity 1016
Diversity of T-cell receptors
Which strategies exist to avoid
recognition of self-antigens?
Selection of T-lymphocytes in the Thymus
Negative selection of T-lymphocytes binding to self antigens with high affinity
Cells binding to self antigens die by apoptosis
Positive selection on ability of binding to MHCI and MHCII molecules
Cells with no affinity to MHC die by apoptosis
Immature DCs are specialized in engulfment of
antigens and present peptides of the digested
proteins on MHC molecules
Presentation of antigen by dendritic cells
MHC class I MHC class II
Expression by cell type all nucleated cells on antigen presenting
cells
Interaction with T-cell
subsets
CD8 cytotoxic T-cells CD4 T-helper cell
Genloci HLA-A, B and C HLA-DR, DP and DQ
Molecular structure a-chain associated with
b2-microglobulin
a-chain associated with
b-chain
Peptides presented 8-10 amino acids larger than 13AA
Intracellular Location Endoplasmatic Reticulum Endosomes
Characteristics of MHC molecules
On MHC class I peptides were presented that are
derived from intracellularly synthesized proteins
Virus infecting
cell
Presentation of peptides on MHC I to T-
Lymphocytes
Peptide
Cell membrane
Cell membrane
Extracellular Proteins
engulfed by antigen
Presenting cell
APC
On MHC class II peptides were presented that are
derived from extracellular sources
Presentation of peptides on MHC II to T-
Lymphocytes
Peptide
Cell membrane
Cell membrane
Anergy: Recognition of antigen without costimulation
APC APC
T-helper-cell Cytotoxic T-cell
Interaction between LFA-1 and ICAM-1 leads to
stabilization of interaction between T-cells and
Antigen Presenting Cell (APC)
Interaction between CD4 and MHCII or CD8 and MHCI
amplifies the signal given by interaction of the MHC-Peptide
complex with the TCR
Interaction of Co-stimulatory molecule
CD80/86 with CD28 is essential for optimal
activation of effector T-cells
Intracellular signal transduction
Figure 6-5
Ca2+ activates Calcineurin which in turn activates NFAT
PKC activates NFkB
Figure 8-20
Activation of T-lymphocytes induces production of IL-2
Effector mechanisms of activated T-lymphocytes
Figure 8-34 Cytotoxic T-lymphocytes kill target cells by induction
of apoptosis
Figure 8-34 Cytotoxic T-lymphocytes kill target cells by induction
of apoptosis
The different stages of the activation of CD4 T-lymphocytes
naive CD4-T-Cells
Activated proliferating T-Cell
Activated T-Cell not determined
(TH0)
TH1-Cell TH2-Cell
Activation of
macrophages; B-cells
produce antibodies of
the isotype IgG1
Activation of B-cells they
produce antibodies of
IgE, IgG4; activation of
eosinophilic granulocytes
aus: „Immunologie“, Janeway et al.
Example for the importance of the decision whether Th1 or Th2
response is induced for the outcome of disease
Leprosy
Tuberculoid Leprosy Lepromatous Leprosy
Mycobacterium
leprae-Infection
M leprae resides in vesicles
of macrophages; macro-
phages were activated by
Th1-cells leading to control
of microbial burden;
only few bacteria detectable
in blood, low antibody titre;
Inflammation of skin and
Nerves but patients survive!
Uncontrolled growth of
M. leprae in macrophages;
Th2-cells do not activate
macrophages; however they
induce production of non
protective antibodies;
disease resulting in massive
destruction of tissue
often resulting in fatal
outcome
Th0
Th2
Th1
+
Mast/Baso
IL-4
DC
IL-12
+
IL-4
IFN-g
-
-
Differentiation of Th1 or Th2 lymphocytes
The immune response to cells infected with bacteria
is coordinated by Th1 Lymphocytes
activated TH1-cell
IFN-g
Activation of
macrophages
leading fusion
of lysosomes
and
phagosomes
Fas-Ligand
oder TNF-b
Killing of
infected cells
by apoptosis
IL-2
Autocrine
mechanism
proliferation
of T-cells
IL-3 + GM-
CSF
Generation of
macrophages
and DCs in
bone marrow
TNF-a
Activation of
endothelium
to attract
macrophages
TH2-cells are important for amplification of B-cell responses
and involved in defense against parasites
activated TH2-cell
Autocrine
stimulation of
T-cell
proliferation,
paracrine
stimulation of
B-
lymphocytes
IL-4
Activation of
B-lymphocytes
Isotype switch
to IgG4 and
IgE, triggering
of Th2
immunity while
suppression of
Th1 immunity
Proliferation
and activation
of eosinophilic
granulocytes
Regulation of
immune
response
IL-2
IL-5
IL-10
IL-13
Activation and
proliferation of
B-lymphocytes
But in the last years several new
subpopulations of T-helper cells were
described….
O´Shea&Paul 2010. SCIENCE 327:1098
Th0 Th17 IL-17 +
IL-6
TGFb
IL-23
IL-8 IL-6
Neutrophilic
Granulocytes
Th17 cells are important for elimination of
fungal infections
Fibroblast IL17R
Th0 Treg
IL-10
TGF-b
+
IL-10
Regulatory T-helper cells are important for
down regulation of the immune response
Inflammation ↓
T-cells ↓
