Download T cells

T cells.
Phenotype, function,
fallacies.
Jan Novák
T cells
 Central role in the immune system
 Recognition of antigens
 Direct effect on the antigens
 Coordination of the immune response
 Suppression of the immune responses
T cells versus B cells
 Minimal morphological
differences
 Differentiation based on the
detection of surface markers
 B cells: CD19, B220,
 T cells: TCR, CD3, CD4,
CD5, CD8 etc.
Phenotype of T cells
 T cell receptor (TCR)
 Other receptors involved in the antigen recognition
and signalization (CD4, CD8, CD3)
 Receptors and molecules involved in the migration of
T cells
 Receptors for cytokines
 Activation markers (CD25, CD28, CD69)
Groups of T cells
  T cells
 T-helpers (CD4+)






Th1
Th2
Th3
Cytotoxic T cells (CD8+)
NKT cells
Regulatory T cells (CD4+CD25+)
  T cells
CD4+ T lymfocyty – T helpers
Th1
IL-12
Th0
Th0
APC
Th2
IL-4
TGF-
TGF- + IL-6
Th3
Th17
Th1 cells
 Inflammatory cells
 Help to macrophages


Activation, stimulation of their killing activities
 Elimination of intracellular agents
 Help to T cells

Proliferation, Th1 differentiation
 Production of cytokines (IFN-, TNF-, IL-2)
Th1 cells
 Clearance of
intracellular pathogens
 Delayed type of
hypersensitivity
 Autoimmune diseases
Th2 cells
 Help to B cells


Development
Antibody production
 Regulatory functions
 Production of cytokines (IL-4,IL-5,IL-6,IL-13)
Th2 cells
 Defense against
extracellular agents
 Participation in
allergic reactions
Th3
Th3 cells
 Develop in the presence of TGF-, IL-10 and IL-4
 Secretion of TGF- and IL-10
 Induced after oral administration of antigens, play a
role in the induction of oral tolerance
Th3
Th17
 Development in the presence of TGF-b a IL-6,
IL-21, IL-23
 Secretion of IL-17, IL-21, IL-22
 Proinflammatory cytokines
 Role in the immune defense against Klebsiella a
citrobacter
 Contribution ion the pathogenesis of some
organ-specific autoimmune diseases in
experimental model
Th3
Cytotoxic CD8+ T cells
 Elimination of dangerous cells of the body
 Elimination of cells infected by intracellular
pathogens
 Elimination of stressed cells (tumors,
damaged cells)
Killing by CD8+ T cells
 Perforin-granzyme system (degranulation,
perforation, apoptotic death)
 Fas-FasL interaction (apoptotic death)
 Cytokine dependent -lymphotoxin (apoptotic
death)
CD8+ T cells in immune reactions
 Clearance of infection
 Onco-immunosurveillance
Regulatory T cells
 CD8+ T cells are not supressors!!!
 CD4+CD25+ T cells
 Th3 T cells
 T reg cells
 NKT cells
  T cells
Functions of regulatory T cells
 Inhibition of the immune responses
 Maintenance of immunological tolerance
 Regulation of exagerated reaction against
infection
 Supresssion of anti-tumor responses
Functions of regulatory T cells
 Cell-contact dependent mechanisms
 Secretion of cytokines (IL-4, IL-10, TGF-)
 Killing of effector cells
NK cells
 NK = natural killer
 Large granular lymphocytes
 Development in bone marrow
Immune reactions of NK cells
 Functions antigen-non specific
 Recognition of unknown structures on the
surface of target cells
Immune reactions of NK cells
 The function of NK cells is a result of the
interaction of their inhibitory and activation
receptors
 Activation: Fc receptor CD16
 ADCC – antibody-dependent cellular
cytotoxicity
 Inhibition – killer inhibitory receptors (Ly49,
CD94-NKG2)
Immune reactions of NK cells
 Cytotoxicity – perforin-granzyme dependent
Immune reactions of NKT
cells
 Natural Killer T cells
 Phynotypic and functional features of both NK
and T cells
Immune reactions of NKT
cells
 Natural Killer T cells
 Phynotypic and functional features of both NK
and T cells
 Restriction by MHC class I like molecule
CD1d presenting glycolipids and lipids
Phenotype of NKT cells
 Expression of TCR, CD3, CD4
 Expression of markers of NK lineage
 Biased TCR repertoire
 Recognition of conserved glycolipid structure
presented by CD1d
Functions of NKT cells
 Secretion of both, Th1 and Th2 cytokines
 Impact on Th1/Th2 differentiation of naive T cells
 Activation of B cells
 Activation of NK cells
 Activation of dendritic and other ather antigen
presenting cells
 Cytotoxic functions
 Regulatory functions
T cells in the development of
diseases
 Defence against infection -
immunodeficiencies
 Allergic reactions
 Autoimmunity
 Oncological diseases
Immunodeficiencies
 Primary (SCID, RAG, common  chain)
 Secondary (HIV, tumors, metabolic disorders,
malnutrition, sepsis)
Immunodeficiencies clinical features
 Life-threatening – asymptomatic relapsing
infections (viruses, fungi, intracellular
bacterias)
Human immunodeficiency virus
 Retrovirus, RNA virus
 Targets selectively
CD4+ T cells,
macrophages and
dendritic cells
HIV infection
 1. 3-12 weeks after infection: Flu-like
syndrom
 2. Asymptomatic period, decrease of
CD4+ T cells, production of anti-HIV
antibodies
HIV infection
 3. AIDS related
complex:
generalized
lymphadenopaty,
diarrhoe,
candidiasis, fever
HIV infection
 4. AIDS: infekce
oportunními patogeny
pneumocysty,
kryptokoky,
toxoplazmoza, CMV
retinitis, enteritidis,
pneumonitis, encefalitis,
maligní nádory Kaposhi sarkom,
primární lymfom mozku,
NHL B, HIV
encefalopatie
Allergic and hypersensitive reactions
 Type 1 of immunopotahologic reactions
 Pathological production of IgE antibodies
 1.: binding of IgE on mast cells and bazofiles,
degranulation and histamine, bradykinine release 
oedema
 2.: eozinofiles, Th2 cells – secretion of leukotriens a
prostaglandines  smooth muscle constriction
 Participation of Th2 and NKT cells, production of IL-4,
IL-13.
Allergic and hypersensitive reactions
 Evolutionary – reactions
against worms and
parazites
 Allergic reactions –
orms, parazites, dust,
food antigens…
Autoimmunity
 Reaction of the immune system against body-
own tissues
 Failure of the immune system to eliminate
autoreactive T cells (central, peripheral
tolerance).
Autoimmune diseases
 Th1 biase of autoreactive T cells
 Prevention of the disease by Th2 switching
 Participation of Th1 and CD8+ T cells in
tissue destruction by cytotoxic mechanisms
and cytokines
Autoimmunity
 Decreased numbers and impaired function of
regulatory T cells in experimental animals and
patients suffering from autoimmune diseases
Oncoimmunology
 The immune system has the
capacity to detect and to
destroy tumor cells
 The animals deficient in T
cells develop tumors in
increased frequencies
 Increased incidence of
tumor in immunosupprimed
patients
Why immune system does not
destroy all tumor cells?
 The same HLA phenotype
 Impaired antigen presentation by tumor cells
 The selection of less immunogenic cells in
the tumor
 Production of immunosuppressive factors by
tumor cells
Can we treat oncologic patients by the
manipulation of the immune system?
 Detection of Tu-specific or Tu-associated
antigens

CEA, -fetoprotein, MAGE
Can we treat oncological patients by the
manipulation of the immune system?
 Immunostimulation
 Vaccines based on
the enhancement of
Tu presentation
 In vitro expansion of
Tu Ag specific T
lymphocytes
Vaccines against oncological
disorders
 Cancer of cervicis uteri
 Vaccination against papilomaviruses
Literature
 Immunobiology – The immune system in
health and disease: Charles A. Janeway Jr.,
Garland Publishing, 2001
 The autoimmune diseases: Noel A. Rose,
Academic Press – Third edition, 1998
 Medical Immunology: Tristam G. Parslow,
Lange – Tenth edition, 2001
 Nature Reviews Immunology