1. CELL-MEDIATED
SPECIFIC
IMMUNITY

2. PLAY A CENTRAL REGULATORY AND EFFECTOR ROLE IN THE IMMUNE SYSTEM
T CELLS:
PLAY A CENTRAL REGULATORY
AND EFFECTOR ROLE IN THE IMMUNE SYSTEM
Regulation:
is mediated by cytokines and cell-to-cell contact
B cells and immunoglobulin production
T cell cytotoxicity
natural killer cells (NK)
cell chemotaxis
 Effector function:
T cell mediated specific cytotoxicity

3. DIFFERENTIATION OF T CELLS
plays in thymus
cell-to-cell contact with epithelial
and dendritic cells
humoral factors
  thymic hormones:
small peptides
thymosine, thymopoetin
immunomodulation

4. THE MOST IMPORTANT EVENTS IN INTRATHYMIC DEVELOPMENT OF T CELLS
T cells in thymus:
proliferate and differentiate
(functional cell-surface molecules)
rearrange genetic information coding TcR
express TcR heterodimers on the surface
induction of self tolerance is generated

5. DIFFERENTIATION OF T CELLS
migration in to thymus is non-random (homing)
      humoral chemotactic factors (chemokines)
      specific surface interactions
differentiation is characterized by:
      migration from subcapsular sinus into medulla
      proliferation
      morfological changes
      changes in surface molecules
majority of thymocytes is dying by apoptosis
due to differentiation failure

6. MEMBRANE MOLECULES OF T CELLS
receptors for antigen: heterodimers TcR, TcR
pan T cells: expressed on all T cells (CD7, CD2, CD3)
subpopulations: helper inducer T cells CD4+
suppressor cytotoxic T cells CD8+
other subsets: thymocytes (CD1)

7. FUNCTION OF SURFACE MOLECULES:
recognition (TcR)
activation signals transmission (CD3)
activation (HLA DR, IL-2R)
accessory (CD4, CD8)
costimulatory (CD28, CTLA-4)
adhesion (CD2)
       

8. SURFACE MOLECULES OF T CELLS :
recognition of Ag
TcR
accessory
molecules
CD4
(CD8)
CD3
adhesion
molecules
CD2
receptors
for
cytokines T
cell
ICAM1
CD69 g b
IL-2R
CD28 a
CD25
activation
molecules b
costimulatory
molecules a
CTLA 4
HLA II.

9. RECEPTORS FOR ANTIGEN ON T CELLS (TcR)
are surface molecules responsible for specific
recognition of antigen which is processed in APC
and presented in association with self HLA I (II) molecules
heterodimer, member of immunoglobuline
family (domain)
pre TcR is premature form of TcR found on thymocytes
majority of mature T cells express  heterodimer
minority of mature T cells express  heterodimer

10. RECEPTORS FOR ANTIGEN ON T CELLS (TcR)
variable TcR domain:
      unique amino acids composition
in antigen-combining site
      weak chemical forces between binding
site of TcR and antigenic peptide are formed

11. RECEPTOR FOR ANTIGEN ON T CELLS (TcR)
DNA V
a (g)
b (d) V S S D S S D J J S S C C S S S S

12. BASIC IMMUNOLOGICAL REPERTOIR OF TcR
      enormous number of T cells with different TcRs
      approx. 1x1016 different TcR specifities in theory
      overloading of theoretical coding capacity of genom
      genetic information for TcR is specifically organised
into gene segments
      genetic information for TcR is specifically processed
(gene rearrangement)

13. REARRANGEMENT OF TcR GENE SEGMENTS
n = hundreds
n = tens
n = single 3´ C 5´ V1 V2 Vn D1 D2 Dn J1 Jn 12 23 V3 J1 7 J2
RAG -1,2 J3 V4 Vn V1 V2 9 D1 D2
rearrangement D3 J1 Jn 3´ C 5´
DNA V1 D3 J1 J2 Jn
transcription
splicing
mRNA N C
translation
VARIABILE
CONSTANT
TcR  chain

14. BASIC REPERTOIR OF TcR IS INCREASED BY
uncorrected joining of V (D) gene segments
to  J genes
random insertion of nucleotides
in to D-J region (enzyme TdT)
unsuccesful rearrangement induces
apoptosis of thymocytes

15. EXPRESSION OF TcR
TcR are expressed on cell in association with  CD3 complex
- TcR: small cytoplasmic part
- CD3: trimolecular complex
- noncovalently associated with TcR
- transmission of activation signals in to cell
- ITAM: Immunoreceptor Tyrosin-based
Activation Motif
phosphorylation of tyrosine (kinases)
- CD4: lck kinase
- costimulatory interactions:
- CD28, CTLA-4  B7.1, B7.2
- critical level of activation signals is necessary
to start T cell activation and clonal expansion

16. TcR - CD 3 COMPLEX ON T CELLSa b
CD 3 COMPLEX S S V S S g d e S S S S S C S S S S S   S S S S I T A M I T A M
ITAM: Immunoreceptor Tyrosin-based Activation Motif

17. IMMUNE RECOGNITION ACTIVATION OF T CELL
clonal expansion
effector functions
anergy
apoptosis
no effect
 Krejsek, 2004

18. INTERACTIONS BETWEEN T CELL AND APC CELL
adhesion interaction
ICAM-1
clonal
expansion
LFA-1
accessory interaction
endogenous
antigen
LFA-3
CD2
signal II
processing:
peptide+ HLA I
costimulation
CD28 B7
transcription
factors
CD4
lck
signal I
PRESENTATION
HLA II
TcR a b P 
STAT g
CD3
STAT d e
JAK P
processing :
peptide+ HLA II
cytokines
exogenous
antigen

19. clonal expansion „context“ + = Ist signal = IInd signal activation of
T CELLS RECOGNIZE ANTIGEN SPECIFICALLY IN „CONTEXT“
COSTIMULATORY INTERACTIONS
„context“
(„danger patterns“)
-accessory interactions
- cytokine microenvironment
= IInd signal
COGNITIVE INTERACTION:
TcR, HLA-Ag, CD4 (CD8)
= Ist signal +
activation of
T cells
clonal expansion
Tcells
Bcells
migration NK
effector and regulatory functions

20. INDUCTION OF SELF TOLERANCE
Basic immunological repertoir of TcRs is generated:
      randomly
      in advance
      without presence of Ags
      in embryonal life
      in thymus
 Basic immunological repertoir of TcRs includes clones
with high probability of self-recognition (autoreactive)
of T cells.
Autoreactive clones of T cells have
to be eliminated by selection.

21. SELECTION:
POSITIVE SELECTION :
T cell clones are tested for affinity (not recognition)
of self HLA I, II molecules
NO AFFINITY: SELECTION (DELETION)
NEGATIVE SELECTION :
T cell clones are tested for recognition of self molecules
quantitative phenomena
EFFECTIVE RECOGNITION: SELECTION (DELETION)
Mature T cell: toleration of self
recognition of non-self.

22. REGULATORY AND EFFECTOR SUBSETS OF T CELLS
mature T cells (TH0) differentiate into functionally distinct
subsets after antigen stimulation
presentation
of microbial. Ag
(LPS, CpG, lipoteichoic a.)
dendritic c., macrophage,
intensive, long term
IL-12
presentation of
environmental. Ag
nonmicrobial origin
(allergens)
B-cells,
weak, short term
IL-4
TH0
INHIBITION
INF
IL-4
TH1
TH2
TH1
TH2
TH1
TH2
cytotoxic reactivity
antibodies production, isotypic switching

23. TH SUBSETS - CYTOKINES PRODUCED
(T reg.)
TNF
INF
TGF 
IL-2
IL-10
G-CSF
IL-6
IL-5
IL-4

24. protective immunity against particular agent
PHYSIOLOGICAL IMMUNE RESPONSE DURING INFECTION
IS REGULATED BY OPTIMAL BALANCE BETWEEN
TH1 AND TH2 SUBSETS.
protective immunity against particular agent
could be either TH1 or TH2 driven
there are subsequent waves of both TH1 and TH2
reactivities in the course of natural infections
implication for vaccine development

25. predominant TH pattern could be delineated for
IMMUNOPATHOLOGY:
predominant TH pattern could be delineated for
particular immunopathological diseases
(TH1multiple sclerosis,TH2  atopy)
the immunopathology –driven inflammation is
regulated by the mix of both subsets activities