T – lymphocytesT – lymphocytes

J. J. OchotnáOchotná

T lymphocytesT lymphocytes T lymphocytes are the cellular component of T lymphocytes are the cellular component of

antigen-specific mechanisms in the ontogenesis antigen-specific mechanisms in the ontogenesis leaving the bone marrow and migrate to the thymus leaving the bone marrow and migrate to the thymus where they maturewhere they mature

There are several different There are several different subsetssubsets of T lymphocytes of T lymphocytes

Participate in the regulation of immune processes, Participate in the regulation of immune processes, the destruction of virus-infected cells or tumor cells the destruction of virus-infected cells or tumor cells

Recognize antigen processed and presented by the Recognize antigen processed and presented by the APC, through the APC, through the TCRTCR recognize complex recognize complex MHC gp -MHC gp -antigenic peptide antigenic peptide

T cells are after activation stimulated to T cells are after activation stimulated to multiplication and differentiation into multiplication and differentiation into effector cellseffector cells and part of them differentiate into the and part of them differentiate into the memory cellsmemory cells

T-lymphocytes ontogenesisT-lymphocytes ontogenesis T cells originate in bone marrow and then migrate to the thymus

where they mature (T lymphocytes), the final differentiation is after activation by antigen processed and presented by APC

T cells can develop outside the thymus (the minority population)

Pluripotent hematopoietic stem cells

Pro-thymocytes - are coming from the bone marrow to the thymus, where they begin to rearrange TCR genes, expressing on their surface, called pre-TCR (Composed of chain, pre-TCRand CD3 complex), then begin rearrange the TCR genes

Cortical thymocytes - express on their surface TCR (composed of chains and CD3) and CD4 and CD8 co-receptor (double positive T lymphocyte), at this stage occurs the selection of autoreactive cells and cells with dysfunctional TCR

Medullary thymocytes (mature T cell) - retain the expression of CD4 or CD8, then migrate to secondary lymphoid organs

T-lymphocytes selectionT-lymphocytes selection Negative selectionNegative selection - the elimination of - the elimination of autoreactiveautoreactive cells, cells,

when thymocytes binds enough strongly by their TCR when thymocytes binds enough strongly by their TCR complex of MHCgp with normal peptides (from complex of MHCgp with normal peptides (from autoantigens)which are presented on surface of thymic cells autoantigens)which are presented on surface of thymic cells thymocyte receives signals leading to apoptotic cell death thymocyte receives signals leading to apoptotic cell death PAE cellsPAE cells (peripherial antigen expressing cells) (peripherial antigen expressing cells)

Positive selectionPositive selection - the elimination of cells with - the elimination of cells with dysfunctional TCRdysfunctional TCR, , positively are selected thymocytes that recognize MHC gp positively are selected thymocytes that recognize MHC gp with low affinity, then maintain the expression of CD4 or CD8 with low affinity, then maintain the expression of CD4 or CD8 (depending what class of MHC gp binds to the TCR). These (depending what class of MHC gp binds to the TCR). These mature T cellsmature T cells (Medullary thymocytes) leave the thymus and (Medullary thymocytes) leave the thymus and migrate to secondary lymphoid organs migrate to secondary lymphoid organs

98% of pro-thymocytes in the thymus during its development 98% of pro-thymocytes in the thymus during its development dies dies

T-lymphocytes surface markersT-lymphocytes surface markers

TCRTCR - recognizes Ag peptide complexed with MHC gp - recognizes Ag peptide complexed with MHC gp

CD3CD3 - TCR component, participation in signal transduction - TCR component, participation in signal transduction

CD4CD4 or or CD8CD8 - co-receptors, bind to MHC gp - co-receptors, bind to MHC gp

CD28CD28 - costimulatory receptor, binds to CD80, CD86 - costimulatory receptor, binds to CD80, CD86

CTLA-4CTLA-4 (CD152) - inhibitory receptor, binds to CD80, CD86 (CD152) - inhibitory receptor, binds to CD80, CD86

T-lymphocytes subpopulationsT-lymphocytes subpopulations

-T lymphocytes-T lymphocytes - have TCR - have TCR, major type , major type (95%), thymus need in development, recognize (95%), thymus need in development, recognize antigens in the complex MHC-peptide gp antigens in the complex MHC-peptide gp

-T lymphocytes-T lymphocytes - (5%) may develop outside the - (5%) may develop outside the thymus, some are able to recognize native Ag, thymus, some are able to recognize native Ag, apply in defense of the skin and mucous apply in defense of the skin and mucous membranes membranes

Intraepithelial T lymphocytesIntraepithelial T lymphocytes

NK-T cellsNK-T cells - recognize complexes of CD1 - recognize complexes of CD1 molecules with lipids molecules with lipids

T-lymphocytesT-lymphocytes

Expressing the CD4 co-receptorExpressing the CD4 co-receptor (co-receptor for (co-receptor for MHC class II gp), precursors of MHC class II gp), precursors of helper T cells (Thelper T cells (THH)),, they can be classified according to the production of they can be classified according to the production of cytokines cytokines

TTHH00 - produce a mixture of cytokines such as T - produce a mixture of cytokines such as THH1 and 1 and TTHH22

TTHH11 - IL-2, IFN - IL-2, IFN (help macrophages ) (help macrophages ) TTHH22 - IL-4, IL-5, IL-6, IL-10 (B lymphocytes assistance) - IL-4, IL-5, IL-6, IL-10 (B lymphocytes assistance)

TTHH33 - TGF - TGF

TregTreg - regulatory T cells arise in the thymus from a - regulatory T cells arise in the thymus from a part part of autoreactive lymphocytes, suppress the activity of of autoreactive lymphocytes, suppress the activity of TTHH1 and partly function as T1 and partly function as TSS, suppression of , suppression of autoreactive T cell clonesautoreactive T cell clones

T-lymphocytesT-lymphocytes

Expressing the CD8 co-receptorExpressing the CD8 co-receptor (co-receptor (co-receptor for MHC gp class I), for MHC gp class I), precursors of cytotoxic T precursors of cytotoxic T cells (TC)cells (TC), or , or suppressor T cells (TS)suppressor T cells (TS)

TTCC - recognize cells infected by viruses or other - recognize cells infected by viruses or other intracellular parasites and some cancer cells intracellular parasites and some cancer cells

TTSS - inhibit the function of other lymphocytes - inhibit the function of other lymphocytes

TCRTCR

TCR (T cell receptor) is heterodimer TCR (T cell receptor) is heterodimer consisting of consisting of and and ( () chain) chain and associated and associated CD3 complexCD3 complex, which is necessary for signal , which is necessary for signal transfer (is connected with PTK) transfer (is connected with PTK)

"N-terminal parts of "N-terminal parts of and and ( () chain form the ) chain form the binding site for Ag binding site for Ag

T lymphocytes T lymphocytes recognize a complex of MHC gp - recognize a complex of MHC gp -Ag peptide on the surface of APC, in the recognition Ag peptide on the surface of APC, in the recognition TCR coopetrate with co-receptor CD4 (helps bind MHC TCR coopetrate with co-receptor CD4 (helps bind MHC gp II) or CD8 (helps bind MHC gp I) gp II) or CD8 (helps bind MHC gp I)

Activation through the TCR and CD28 leads to Activation through the TCR and CD28 leads to proliferation and differentiation into effector cells proliferation and differentiation into effector cells

CD28CD28 - costimulating receptor, binds ligands CD80 - costimulating receptor, binds ligands CD80 and CD86, which are on the surface of APC and CD86, which are on the surface of APC

TCR cooperation with co-receptors CD4, CD8TCR cooperation with co-receptors CD4, CD8

Generation of the TCRGeneration of the TCR

The analogy with the formation of BCR The analogy with the formation of BCR

Chains Chains and and - correspond to IgH gene complex of - correspond to IgH gene complex of immunoglobulins immunoglobulins

- V, D, J, C segments - V, D, J, C segments

Chains Chains and and - correspond to genes for L chains of- correspond to genes for L chains of immunoglobulins immunoglobulins - V, J, C segments - V, J, C segments

Rearrangement of genes is similar to the BCR and Rearrangement of genes is similar to the BCR and performed by the same performed by the same recombinasesrecombinases

Sources of variabilitySources of variability - a combination of V (D) J - a combination of V (D) J segments, connecting variability, random sequences , in segments, connecting variability, random sequences , in the genes for TCR no somatic mutations and no affinity the genes for TCR no somatic mutations and no affinity maturation maturation

TTHH1 based immune 1 based immune reactionreaction

TTHH1 based immune reaction 1 based immune reaction

- inflammatory reaction- inflammatory reaction The basic function of TThe basic function of THH1 cells is 1 cells is cooperation with macrophagescooperation with macrophages

and their transformation in activatedand their transformation in activated, which are capable to , which are capable to produce NO through which destroy its intracellular parasitesproduce NO through which destroy its intracellular parasites

For the conversion to activated macrophages are essential For the conversion to activated macrophages are essential cytokines (IFNcytokines (IFN) produced by T) produced by THH1 cells1 cells

Activated macrophages secrete some cytokines (IL-1, TNF, ...) that Activated macrophages secrete some cytokines (IL-1, TNF, ...) that help to stimulate T cells and help to stimulate T cells and stimulate local inflammationstimulate local inflammation, which , which helps suppress infection helps suppress infection

Interaction between TInteraction between THH1 cells and macrophages is a fundamental 1 cells and macrophages is a fundamental mechanism of delayed-type immunopathological reactions (DTH mechanism of delayed-type immunopathological reactions (DTH Delayed-type hypersensitivity) Delayed-type hypersensitivity)

The infected macrophage produces protein fragments The infected macrophage produces protein fragments derived from intracellular parasites, some of which derived from intracellular parasites, some of which are presented on the surface by are presented on the surface by MHC gp class IIMHC gp class II

Macrophages and dendritic cells stimulated by certain Macrophages and dendritic cells stimulated by certain microorganisms produce microorganisms produce IL-12IL-12

TTHH precursor precursor, which detects the infected macrophage , which detects the infected macrophage and receives signals through the and receives signals through the TCR, CD 28TCR, CD 28 and and receptor for IL-12receptor for IL-12 and other adhesion and signaling and other adhesion and signaling molecules proliferates and differentiates to the molecules proliferates and differentiates to the effector Teffector THH1 cells1 cells that produce that produce IFNIFN and and IL-2 IL-2. .

IFNIFN promotes transformation of macrofages in promotes transformation of macrofages in activated activated IL-2IL-2 is an autocrine growth factor for T is an autocrine growth factor for THH1 1 cells cells

Interaction between APC and TInteraction between APC and THH precursor precursor

Interaction between APC and T cellInteraction between APC and T cell

TTHH2 based immune 2 based immune reactionreaction

TTHH2 based immune reaction 2 based immune reaction – helping to B-lymphocytes– helping to B-lymphocytes

The basic function of TThe basic function of THH2 cells is the 2 cells is the cooperation cooperation with B lymphocyteswith B lymphocytes (which were stimulated by Ag) (which were stimulated by Ag) by cytokines (IL-4, IL-5, IL-6) and direct intercellular by cytokines (IL-4, IL-5, IL-6) and direct intercellular contact contact

For stimulation of B lymphocytes is usually For stimulation of B lymphocytes is usually necessary cooperation between necessary cooperation between APC → TAPC → THH2 cell → B 2 cell → B lymphocytelymphocyte

In the case of the In the case of the minimal modelminimal model, where the B cell , where the B cell becomes a good APC (CD80, CD86) is sufficient becomes a good APC (CD80, CD86) is sufficient cooperation between cooperation between TTHH2 cell → B lymphocyte2 cell → B lymphocyte

TTHH precursor precursor, which detects the infected , which detects the infected macrophage and receives signals through the macrophage and receives signals through the TCR, CD 28 receptor for IL-4TCR, CD 28 receptor for IL-4 receptor and IL-2 and receptor and IL-2 and other adhesion and signaling molecules other adhesion and signaling molecules proliferates and differentiates in the proliferates and differentiates in the effector Teffector THH22, , which provide B lymphocytes auxiliary signals via which provide B lymphocytes auxiliary signals via cytokines secreted by cytokines secreted by IL-4, IL-5, IL-6IL-4, IL-5, IL-6 and adhesion and adhesion molecules through molecules through CD 40LCD 40L, which bind to the , which bind to the costimulatory receptor on B lymphocytes CD 40 costimulatory receptor on B lymphocytes CD 40

Interaction between Interaction between CD40 (B lymphocytes) and CD40 (B lymphocytes) and CD40L (TH2 cells)CD40L (TH2 cells) is essential for the initiation of is essential for the initiation of somatic mutations, izotype switching and somatic mutations, izotype switching and formation of memory cells formation of memory cells

IL-4, IL-5, IL-6IL-4, IL-5, IL-6: stimulation of B lymphocytes : stimulation of B lymphocytes

Assistance to B lymphocytesAssistance to B lymphocytes

Specific direct assistance to B lymphocytes:Specific direct assistance to B lymphocytes:

TTHH2 lymphocytes assisting B lymphocytes that were 2 lymphocytes assisting B lymphocytes that were stimulated by the same Ag, which caused the rise of stimulated by the same Ag, which caused the rise of TTHH2 2

To stimulate the secretion of cytokines by TTo stimulate the secretion of cytokines by THH2 cell is 2 cell is sufficient signal via the TCR (signal through a sufficient signal via the TCR (signal through a costimulatory receptor CD28 is no longer necessary) costimulatory receptor CD28 is no longer necessary)

One clone of TOne clone of THH2 cells can provide specific assistance 2 cells can provide specific assistance to B lymphocytes of different specificities (must to B lymphocytes of different specificities (must present the relevant Ag peptides by MHC gp II, which present the relevant Ag peptides by MHC gp II, which are recognized by TCR) are recognized by TCR)

Assistance to B lymphocytesAssistance to B lymphocytes

Indirect assistance to B cells ("bystander help"):Indirect assistance to B cells ("bystander help"):

TTHH2 lymphocytes assisting B lymphocytes that 2 lymphocytes assisting B lymphocytes that were stimulated by another Ag than that which were stimulated by another Ag than that which caused the rise of Tcaused the rise of THH2 2

Contact between TContact between THH2 cell → B lymphocytes2 cell → B lymphocytes via via adhesion molecules, cytokine secretion, binding adhesion molecules, cytokine secretion, binding CD40-CD40L CD40-CD40L

Danger of activation autoreactive B lymphocytes Danger of activation autoreactive B lymphocytes

Mutual regulation of activities TMutual regulation of activities THH1versus 1versus TTHH22

Whether the TWhether the THH precursor cell will develop into T precursor cell will develop into THH1 or T1 or THH2 2 decides decides cytokine ratio of IL-12 and IL-4cytokine ratio of IL-12 and IL-4

IL-12IL-12 is produced by macrophages and dendritic cells is produced by macrophages and dendritic cells stimulated by certain microorganismsstimulated by certain microorganisms

IL-4 IL-4 is produced by activated basophils and mast cells is produced by activated basophils and mast cells

TTHH1 cytokines produced (mainly IFN1 cytokines produced (mainly IFN) inhibit the ) inhibit the development of Tdevelopment of THH2 and stimulate the development of T2 and stimulate the development of THH1 1 (IL-2 stimulates also T(IL-2 stimulates also THH2)2)

Cytokines produced by TCytokines produced by THH2 (IL-4, IL-10) inhibit the 2 (IL-4, IL-10) inhibit the development of Tdevelopment of THH1 and stimulate the development of T1 and stimulate the development of THH2 2

TTHH3 development is stimulated by a specific cytokine 3 development is stimulated by a specific cytokine environment (IL-4, IL-10, TGFenvironment (IL-4, IL-10, TGF); T); THH3 produce TGF3 produce TGF and and cooperate with B cells in MALT cooperate with B cells in MALT

TTCC based immune based immune reactionreaction

Stimulation of cytotoxic T lymphocytesStimulation of cytotoxic T lymphocytes

TTCC recognize cells infected with viruses or other recognize cells infected with viruses or other intracellular parasites, and some tumor cells intracellular parasites, and some tumor cells

Precursor of TPrecursor of TCC, which recognizes a complex , which recognizes a complex of of MHC gp I- antigenic peptideMHC gp I- antigenic peptide on the surface of on the surface of APC via APC via TCRTCR and receives signals via and receives signals via CD 28CD 28 proliferates and differentiates to clone mature proliferates and differentiates to clone mature effector cytotoxic cells (CTL)effector cytotoxic cells (CTL); T; THH1 cells help to T1 cells help to TCC by by production production IL-2IL-2

Effector TEffector TCC are spread by bloodstream into tissues; are spread by bloodstream into tissues; for activation of cytotoxic mechanisms is sufficient for activation of cytotoxic mechanisms is sufficient signal through the TCR (signal through a signal through the TCR (signal through a costimulatory receptor CD28 is no longer costimulatory receptor CD28 is no longer necessary) necessary)

Professional APC are dendritic cells or Professional APC are dendritic cells or

macrophages that are infected with virus, or macrophages that are infected with virus, or

swallowed antigens from dead infected, tumor or swallowed antigens from dead infected, tumor or

stressed cellsstressed cells

In order APC could activate the TIn order APC could activate the TCC precursor, APC precursor, APC

must be stimulated by contact with Tmust be stimulated by contact with THH cells via cells via

CD 40, then the dendritic cell begins to express CD 40, then the dendritic cell begins to express

CD 80, CD86 and secrete cytokines (IL-1, IL-12) = CD 80, CD86 and secrete cytokines (IL-1, IL-12) =

change of resting APC in activated change of resting APC in activated

Effector functions of TEffector functions of TCC

Cytotoxic granulesCytotoxic granules containing containing perforinperforin and and granzymes granzymes (perforin creates pores in the (perforin creates pores in the cytoplasmic membrane of target cell, in some cytoplasmic membrane of target cell, in some cases may lead to osmotic lysis of the target cell, cases may lead to osmotic lysis of the target cell, formed pores in the cell receiving granzymes that formed pores in the cell receiving granzymes that cause the target cell to die by cause the target cell to die by apoptosisapoptosis. .

Fas ligand (FasL)Fas ligand (FasL) - which binds to the apoptotic - which binds to the apoptotic receptor Fas (CD95) presented on the surface of receptor Fas (CD95) presented on the surface of many different cells (also on the surface of Tmany different cells (also on the surface of TCC) )

TNFTNF

Antigen-specific mechanismsAntigen-specific mechanisms

Antibodies based immune Antibodies based immune reactionreaction

Antibody responses induced byAntibody responses induced by

T-independent antigensT-independent antigens Cause predominantly IgM production Cause predominantly IgM production Bacterial polysaccharides, Bacterial polysaccharides,

lipopolysaccharides, and polymeric forms of lipopolysaccharides, and polymeric forms of protein protein

T-dependent antigensT-dependent antigens Reaction to these Ag occurs in two stages - Reaction to these Ag occurs in two stages -

primary and secondary responseprimary and secondary response These reactions may be separated or can be These reactions may be separated or can be

attached to each other attached to each other Initiate the development of Initiate the development of memory cellsmemory cells

and formation of high-affinity antibodiesand formation of high-affinity antibodies

Antibody responses induced Antibody responses induced by antigen-dependent T lymphocytesby antigen-dependent T lymphocytes

Primary phase of antibody responsePrimary phase of antibody response

The first contact with Ag The first contact with Ag

Takes place in secondary lymphoid organsTakes place in secondary lymphoid organs

Stimulation of B cells by Stimulation of B cells by Ag binding to BCRAg binding to BCR

Ag absorption by APCAg absorption by APC and its presentation via MHC gp and its presentation via MHC gp class II to precursors of Tclass II to precursors of THH cell → formation of clone of cell → formation of clone of

antigen-specific Tantigen-specific THH2 cells, which provide assistance to 2 cells, which provide assistance to

competent B lymphocytes, leading to their proliferation, competent B lymphocytes, leading to their proliferation, differentiation into plasma (produce Ab) and memory differentiation into plasma (produce Ab) and memory cellscells

Plasma cellsPlasma cells are spread by bloodstream into the are spread by bloodstream into the organism (particularly bone marrow)organism (particularly bone marrow)

Antibodies produced in the primary stage (3-4 Antibodies produced in the primary stage (3-4 days) are days) are IgMIgM and have a low affinity for Ag, and have a low affinity for Ag, create with Ag immune complexescreate with Ag immune complexes

Immune complexesImmune complexes are captured in the are captured in the secondary lymphoid organs on the surface of FDC secondary lymphoid organs on the surface of FDC (follicular dendritic cells) - Ag presenting cells to (follicular dendritic cells) - Ag presenting cells to B lymphocytes B lymphocytes

Secondary phase of antibody responseSecondary phase of antibody response

Recognition of Ag on FDCRecognition of Ag on FDC

(If is sufficient amount of immune complexes on (If is sufficient amount of immune complexes on FDCs and are recognized by memory B cells) FDCs and are recognized by memory B cells)

Under the influence of signals from the FDC (Ag) Under the influence of signals from the FDC (Ag) and Tand THH2 cells (CD40L, cytokines) is again started the 2 cells (CD40L, cytokines) is again started the proliferation and differentiation of B cells proliferation and differentiation of B cells accompanied with accompanied with somatic mutationssomatic mutations → formation → formation of clones of B cells with new BCR → survive only B of clones of B cells with new BCR → survive only B cells with a BCR with the highest affinity for Ag = cells with a BCR with the highest affinity for Ag = affinity maturation of antibodiesaffinity maturation of antibodies

There is also There is also isotype switchingisotype switching, which isotypes arise , which isotypes arise determines cytokine environment determines cytokine environment

In the secondary phase of the immune response In the secondary phase of the immune response generate generate antibodies with higher affinity for Agantibodies with higher affinity for Ag and other effector characteristics dependent on and other effector characteristics dependent on isotypeisotype, also formed a , also formed a memory cellsmemory cells for next for next meeting with the Ag meeting with the Ag

Antibodies in the body after primary infection Antibodies in the body after primary infection persist for a long time persist for a long time

Contact between Contact between CD40CD40 (B lymphocytes) and (B lymphocytes) and CD40LCD40L (T (THH2 lymphocytes) is essential for the 2 lymphocytes) is essential for the initiation of initiation of somatic mutations, isotype switching somatic mutations, isotype switching and formation of memory cells and formation of memory cells

Physiological Physiological

mechanisms of mechanisms of

regulation of the regulation of the

immune systemimmune system

Regulation by antigenRegulation by antigen

Induce immune responses and extinctionInduce immune responses and extinction

Affinity maturation of B lymphocytes Affinity maturation of B lymphocytes

Maintaining immunological memoryMaintaining immunological memory

Antigenic competition Antigenic competition

Threshold density of the complex MHC II-gp Ag on Threshold density of the complex MHC II-gp Ag on APC APC

Regulation by antagonistic peptidesRegulation by antagonistic peptides

AgonistAgonist - antigenic peptide, which induce full T - antigenic peptide, which induce full T cell response (proliferation, differentiation, Tcell response (proliferation, differentiation, THH or or TTCC and stimulation of effector functions) and stimulation of effector functions)

AntagonistAntagonist - (partial agonist) peptide structurally - (partial agonist) peptide structurally similar to antigen-peptide, which induce similar to antigen-peptide, which induce qualitatively different response of T lymphocytes qualitatively different response of T lymphocytes (production of only some cytokines, anergy, ...) (production of only some cytokines, anergy, ...)

Negative signals induced by antagonist may Negative signals induced by antagonist may overcome positive signals induced by agonist overcome positive signals induced by agonist (which is in the body in excess), it is used by (which is in the body in excess), it is used by some microorganisms some microorganisms

Regulation by antibodiesRegulation by antibodies

Antibodies competes with the BCR for antigen Antibodies competes with the BCR for antigen (negative regulator of B lymphocyte stimulating) (negative regulator of B lymphocyte stimulating)

IgG immune complexes bind to the BCR and FcIgG immune complexes bind to the BCR and FcR R on B cells, resulting in blocking activation of B on B cells, resulting in blocking activation of B lymphocytes lymphocytes

It is still unclear meaning of regulation via It is still unclear meaning of regulation via idiotypic network idiotypic network

Regulation by cytokines and cellular Regulation by cytokines and cellular contactcontact

Interaction APC - T lymphocyte Interaction APC - T lymphocyte

Interaction TInteraction THH1 – macrophages1 – macrophages

Interaction TInteraction THH2 - B lymphocytes 2 - B lymphocytes

Mutual regulation of activity TMutual regulation of activity THH1 versus T1 versus THH2 2

Development of leukocyte subpopulations Development of leukocyte subpopulations

Negative regulation of effector cells:Negative regulation of effector cells:

CTLA-4 - T cell inhibitory receptor, binds ligands CD80 and CTLA-4 - T cell inhibitory receptor, binds ligands CD80 and

CD86CD86

Inhibitory receptors of NK cellsInhibitory receptors of NK cells

Self-destruction interaction of the apoptotic receptor Fas with Self-destruction interaction of the apoptotic receptor Fas with

ligand FasL on the surface of activated T lymphocytes ligand FasL on the surface of activated T lymphocytes

Suppression mediated by T Suppression mediated by T lymphocyteslymphocytes

Mutual negative interaction TMutual negative interaction THH1 and T1 and THH2 cytokine-mediated (T2 cytokine-mediated (THH2 2 lymphocytes produce IL-4 and IL-10 that suppress the immune lymphocytes produce IL-4 and IL-10 that suppress the immune response based on TH1 cells)response based on TH1 cells)

CD 8CD 8++ T TSS - suppressor T cells has not yet been isolated - suppressor T cells has not yet been isolated as a separate subset (partly identical with T as a separate subset (partly identical with TCC) )               - negatively regulate the activation of other T cells              - negatively regulate the activation of other T cells

Soluble suppressor factors - some CD 8Soluble suppressor factors - some CD 8++ T lymphocytes produce a T lymphocytes produce a soluble form of TCR soluble form of TCR

Clonal elimination or anergy of T lymphocytes after contact with Clonal elimination or anergy of T lymphocytes after contact with antigen on the surface of cells other than APC (lacking antigen on the surface of cells other than APC (lacking costimulating signals)costimulating signals)

Regulatory T cells (TRegulatory T cells (Trr1 CD 41 CD 4++) help to maintain tolerance to ) help to maintain tolerance to autoantigensautoantigens

Neuroendocrine regulationNeuroendocrine regulation Some neurotransmitters act on leukocytes Some neurotransmitters act on leukocytes

(noradrenaline)(noradrenaline)

Direct contact with free nerve endings and mast cells Direct contact with free nerve endings and mast cells (mast cell degranulation in pain) (mast cell degranulation in pain)

Some endocrine hormones act on leukocytes (steroids, Some endocrine hormones act on leukocytes (steroids, growth hormone, thyroxine, endorphins ...) growth hormone, thyroxine, endorphins ...)

Leucocytes produced a number of hormones Leucocytes produced a number of hormones (endorphins, ACTH, TSH, growth hormone ...) (endorphins, ACTH, TSH, growth hormone ...)

Some cytokines act on the nervous system (IL-1, IL-6, Some cytokines act on the nervous system (IL-1, IL-6, LIF, TNF) LIF, TNF)

Influence of emotional stress on the immune system Influence of emotional stress on the immune system

Factors influencing the outcome of the Factors influencing the outcome of the immune responseimmune response

The same antigen can induce an active immune The same antigen can induce an active immune response or an active state of tolerance, the result response or an active state of tolerance, the result of response depends on many factors:of response depends on many factors:

State of the immune systemState of the immune system

Properties of antigen Properties of antigen

Dose of antigenDose of antigen

Route of antigen administration Route of antigen administration

CytokinesCytokines

(Tissue hormones) (Tissue hormones)

CytokinesCytokines

Regulatory proteins and glycoproteins produced Regulatory proteins and glycoproteins produced by leukocytes and other cells by leukocytes and other cells

Essential regulators of the immune systemEssential regulators of the immune system

Apply outside the immune system (angiogenesis, Apply outside the immune system (angiogenesis, tissue regeneration, carcinogenesis, treatment of tissue regeneration, carcinogenesis, treatment of many brain functions, embryonic development ...) many brain functions, embryonic development ...)

Cytokines - secreted Cytokines - secreted      - membrane (CD 80, CD86, CD40L,      - membrane (CD 80, CD86, CD40L, FasL ..) FasL ..)

Pleiotropic effectPleiotropic effect

Operates in a cascadeOperates in a cascade

Cytokine Network Cytokine Network

Cytokine system is redundant Cytokine system is redundant

Effects of cytokinesEffects of cytokines - autocrine - autocrine - paracrine - paracrine

- endocrine - endocrine

Are known as interleukins (exception: TNF, Are known as interleukins (exception: TNF, lymphotoxin, TGF, interferons, CSF and growth lymphotoxin, TGF, interferons, CSF and growth factors) factors)

B cells communicate via cytokines with other

inflammatory cells, such as T cells and macrophages

Overview of cytokinesOverview of cytokines

interleukins (IL-1 and IL-23)interleukins (IL-1 and IL-23)

chemokines (IL-8 and related molecules) chemokines (IL-8 and related molecules)

interferons (IFN-interferons (IFN-) )

transforming growth factors (TGFtransforming growth factors (TGF TGF TGF))

colony stimulating factors (G-CSF, M-CSF, GM-CSF) colony stimulating factors (G-CSF, M-CSF, GM-CSF)

tumors necrosis factors (TNF-tumors necrosis factors (TNF-, lymphotoxin) , lymphotoxin)

other growth factors (SCF, EPO, FGF, NGF, LIF) other growth factors (SCF, EPO, FGF, NGF, LIF)

Distribution of cytokines by functionDistribution of cytokines by function

Proinflammatory cytokines (IL-1, IL-6,IL- 8,IL- 12,IL- 18, TNF)Proinflammatory cytokines (IL-1, IL-6,IL- 8,IL- 12,IL- 18, TNF)

Antiinflammatory cytokines (IL-1Ra, IL-4, IL-10, TGFAntiinflammatory cytokines (IL-1Ra, IL-4, IL-10, TGF))

Cytokines with the activity of hematopoietic cells growth factorCytokines with the activity of hematopoietic cells growth factor (IL-2, 3, 4, 5, 6, 7, 9, 11, 14, 15, CSF, SCF, LIF, EPO) (IL-2, 3, 4, 5, 6, 7, 9, 11, 14, 15, CSF, SCF, LIF, EPO)

Cytokines applying in TCytokines applying in THH2 humoral immunity (IL-4, 5, 9, 13) 2 humoral immunity (IL-4, 5, 9, 13)

Cytokines applying in the cell-mediated immunity TCytokines applying in the cell-mediated immunity THH1 1 (IL-2, 12, IFN (IL-2, 12, IFN, GM-CSF, lymphotoxin) , GM-CSF, lymphotoxin)

Cytokines with anti-virus effect (IFN-Cytokines with anti-virus effect (IFN-, IFN-, IFN-, IFN- , IFN- ))

Cytokine receptorsCytokine receptors Consisting of 2 or 3 subunits Consisting of 2 or 3 subunits

One subunit binds cytokine, other are associated One subunit binds cytokine, other are associated with cytoplasmic signaling molecules (protein with cytoplasmic signaling molecules (protein kinases) kinases)

Signaling subunit is shared by several different Signaling subunit is shared by several different cytokine receptors - called receptor family cytokine receptors - called receptor family

Signaling through these receptors may lead to Signaling through these receptors may lead to proliferation, differentiation, activation of effector proliferation, differentiation, activation of effector mechanisms or blocking the cell cycle and mechanisms or blocking the cell cycle and induction of apoptosis induction of apoptosis