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

IL-12

IL-4

TGF-

Th1

Th2

Th3

Th0 APCTh0

TGF-IL-6

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