CELL-MEDIATED

SPECIFIC

IMMUNITY

 

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

T CELLS: PLAY A CENTRAL REGULATORY

AND EFFECTOR ROLE IN THE IMMUNE SYSTEM

DIFFERENTIATION OF T CELLSDIFFERENTIATION OF T CELLS

plays in thymus cell-to-cell contact with epithelial and dendritic cells

humoral factors

  thymic hormones:

small peptides

thymosine, thymopoetin

immunomodulation

THE MOST IMPORTANT EVENTS IN INTRATHYMIC DEVELOPMENT OF T CELLS

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

DIFFERENTIATION OF T CELLSDIFFERENTIATION 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

 

MEMBRANE MOLECULES OF T CELLSMEMBRANE 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)

 

FUNCTION OF SURFACE MOLECULES:FUNCTION OF SURFACE MOLECULES:

recognition (TcR)

activation signals transmission (CD3)

activation (HLA DR, IL-2R)

accessory (CD4, CD8)

costimulatory (CD28, CTLA-4)

adhesion (CD2)

       

SURFACE MOLECULES OF T CELLS :SURFACE MOLECULES OF T CELLS :

CD69

TcellT

cell

CD3CD3

TcR

CD

2

ICAM1ICAM1

adhesionmolecules

HLA II.

IL-2R

activationmolecules

CD28CD28costimulatory

molecules

receptors

forcytokines

accessorymolecules

recognition of Ag

CD25

CD4(CD8)

CTLA 4

RECEPTORS FOR ANTIGEN ON T CELLS (TcR)RECEPTORS FOR ANTIGEN ON T CELLS (TcR)

are surface molecules responsible for specificrecognition of antigen which is processed in APC and presented in association with self HLA I (II) molecules

heterodimer, member of immunoglobulinefamily (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

 

RECEPTORS FOR ANTIGEN ON T CELLS (TcR)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

RECEPTOR FOR ANTIGEN ON T CELLS (TcR)RECEPTOR FOR ANTIGEN ON T CELLS (TcR)

S

S

S

S

S

S

S

S

TcR

SS

DNA

C

C

VV

DDJ

J

      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)

 

BASIC IMMUNOLOGICAL REPERTOIR OF TcRBASIC IMMUNOLOGICAL REPERTOIR OF TcR

REARRANGEMENT OF TcR GENE SEGMENTSREARRANGEMENT OF TcR GENE SEGMENTS

5´3´ V1V1 V2V2 VnVn D1D1 D2D2 DnDn J1J1 JnJnCC

5´3´ V1V1 D3D3 J1J1CCDNA

mRNA

N C

V3V3

J1

J2

RAG -1,2

J3

RAG -1,2V4V4

Vn

Vn

V1V1 V2V2

D1

D1

D2

D2

D3D3 J1J1 JnJn

J2J2 JnJn

rearrangement

n = hundreds n = tens n = single

transcription

splicing

translationVARIABILEVARIABILE CONSTANTCONSTANT

TcR chain

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 

BASIC REPERTOIR OF TcR IS INCREASED BY BASIC REPERTOIR OF TcR IS INCREASED BY

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

EXPRESSION OF TcR

S

S

S

S

S

S

S

S

TcR

SS

V

CS

S

S

S

S

S

S S

ITAM

ITAM

CD 3 COMPLEX

TcR - CD 3 COMPLEX ON T CELLSTcR - CD 3 COMPLEX ON T CELLS

ITAM: Immunoreceptor Tyrosin-based Activation Motif

IMMUNE RECOGNITION ACTIVATION OF T CELLIMMUNE RECOGNITION ACTIVATION OF T CELL

clonal expansion

effector functions

anergy

apoptosis no effect

Krejsek, 2004

T cellT cell T cellT cell T cellT cell

INTERACTIONS BETWEEN T CELL AND APC CELLINTERACTIONS BETWEEN T CELL AND APC CELL

exogenousantigen

exogenousantigen

endogenousantigen

endogenousantigen

APC

Tcell

adhesion interactionICAM-1

LFA-1

accessory interactionLFA-3

CD2

costimulation

B7CD28

HLA II TcR

CD4

CD3

lck

clonalexpansion

processing:peptide+ HLA I

processing:peptide+ HLA I

processing :peptide+ HLA II

processing :peptide+ HLA II

PRESENTATIONPRESENTATION

STATSTAT

P

PJAK

signal IIsignal II

cytokines

signal Isignal I

transcriptionfactors

T CELLS RECOGNIZE ANTIGEN SPECIFICALLY IN „CONTEXT“T CELLS RECOGNIZE ANTIGEN SPECIFICALLY IN „CONTEXT“

TcellsTcellsBcellsBcells migrationmigration

NKNK

COSTIMULATORY

INTERACTIONS „context“

(„danger patterns“)-accessory interactions

- cytokine microenvironment

= IInd signal

COSTIMULATORY

INTERACTIONS „context“

(„danger patterns“)-accessory interactions

- cytokine microenvironment

= IInd signal

COGNITIVE INTERACTION:

TcR, HLA-Ag, CD4 (CD8)

= Ist signal

COGNITIVE INTERACTION:

TcR, HLA-Ag, CD4 (CD8)

= Ist signal

activation of T cells

activation of T cells

clonal expansionclonal expansion

effector and regulatory functionseffector and regulatory functions

INDUCTION OF SELF TOLERANCEINDUCTION 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 cloneswith high probability of self-recognition (autoreactive)of T cells.

 

Autoreactive clones of T cells have to be eliminated by selection.

SELECTION: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.

 

 

REGULATORY AND EFFECTOR SUBSETS OF T CELLSREGULATORY AND EFFECTOR SUBSETS OF T CELLS

mature T cells (TH0) differentiate into functionally distinct subsets after antigen stimulation

TH1 TH2

presentation of microbial. Ag

(LPS, CpG, lipoteichoic a.)dendritic c., macrophage,

intensive, long termIL-12

presentation of microbial. Ag

(LPS, CpG, lipoteichoic a.)dendritic c., macrophage,

intensive, long termIL-12

presentation of environmental. Ag

nonmicrobial origin(allergens)

B-cells, weak, short term

IL-4

presentation of environmental. Ag

nonmicrobial origin(allergens)

B-cells, weak, short term

IL-4

TH0

INHIBITIONIN

F IL-4

TH1

TH2TH1

TH2

cytotoxic reactivity antibodies production, isotypic switching

TH2TH1TH1

TH3

(T reg.)

TH3

(T reg.)

TNF

INF

TGF

IL-2

IL-10 G-CSF

IL-6

IL-5

IL-4

TH SUBSETS - CYTOKINES PRODUCED TH SUBSETS - CYTOKINES PRODUCED

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

PHYSIOLOGICAL IMMUNE RESPONSE DURING INFECTION IS REGULATED BY OPTIMAL BALANCE BETWEEN

TH1 AND TH2 SUBSETS.

PHYSIOLOGICAL IMMUNE RESPONSE DURING INFECTION IS REGULATED BY OPTIMAL BALANCE BETWEEN

TH1 AND TH2 SUBSETS.

IMMUNOPATHOLOGY:IMMUNOPATHOLOGY:

predominant TH pattern could be delineated for

particular immunopathological diseases (TH1multiple sclerosis,TH2 atopy)

the immunopathology –driven inflammation is

regulated by the mix of both subsets activities