No 13 Immunological Tolerance

8/2/2019 No 13 Immunological Tolerance

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T-cells &

Immunological Tolerance


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Chapter 10.


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Tolerance

Our own bodies produce some 100,000different proteins and one of the longstandingconundrums of immunology has been tounderstand how the immune system

produces a virtual repertoire againstpathogens while at the same time avoidingreacting to self.

The strict definition of immunologicaltolerance occurs when an immunocompetenthost fails to respond to an immunogenicchallenge with a specific antigen.


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Tolerance

The mechanisms the immune system usesto ensure the absence of self-reactivity(autoimmunity) include:

Central Tolerance - this occurs duringlymphocyte development.

Peripheral Tolerance- occurs afterlymphocytes leave the primary lymphoidorgans.


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Central Tolerance


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Peripheral Tolerance


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TOLERANCE

Introduction

Tolerance refers to the specificimmunological non-reactivity to an antigen

resulting from a previous exposure to thesame antigen.

While the most important form of tolerance

is non-reactivity to self antigens, it ispossible to induce tolerance to non-selfantigens. When an antigen inducestolerance, it is termed tolerogen.


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TOLERANCE

Tolerance is different from non-specificimmunosuppression and immunodeficiency.It is an active antigen-dependent process in

response to the antigen. Like immune response, tolerance is specific

and like immunological memory, it can existin T-cells, B cells or both and like

immunological memory, tolerance at the Tcell level is longer lasting than tolerance atthe B cell level.


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Tolerance to tissues and cells

Tolerance to tissue and cell antigens can beinduced by injection of hemopoietic (stem) cellsin neonatal or severely immunocompromised (by

lethal irradiation or drug treatment) animals. Also, grafting of allogeneic bone marrow or

thymus in early life results in tolerance to thedonor type cells and tissues. Such animals are

known as chimeras. These findings are ofsignificant practical application in bone marrowgrafting.


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Tolerance to soluble antigens

A state of tolerance to a variety of T-dependent and T-independent antigenshas been achieved in various experimental

models.

Based on these observations it is clearthat a number of factors determine

whether an antigen will stimulate animmune response or tolerance


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Tolerance

Also see Table 10-1 of text


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Tolerance

Induction of tolerance in T cells is easierand requires relatively smaller amounts oftolerogen than tolerance in B cells.

Maintenance of immunological tolerancerequires persistence of antigen.

Tolerance can be broken naturally (as inautoimmune diseases) or artificially (as

shown in experimental animals, by x-irradiation, certain drug treatments and byexposure to cross reactive antigens).


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Ignorance

It can be shown that there are T cells and Bcells specific for auto-antigens present incirculation.

These cells are quite capable of making aresponse but are unaware of the presence oftheir auto-antigen. This arises for 2 reasons.


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Ignorance

The first is that the antigen may simply bepresent in too low concentration. Since alllymphocytes have a threshold for receptor

occupancy which is required to trigger aresponse then very low concentrations ofantigen (in the case of T cells these are very

low, see below) will not be sensed.


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Ignorance

The second possibility is a more interesting one.Some antigens are sequestered from theimmune system in locations which are not freelyexposed to surveillance.

These are termedimmunologically privilegedsites. Examples of such sites are the eye, CNSand testis.

Pathologically mediated disruption of theseprivileged sites may expose the sequesteredantigens leading to an autoimmune response.


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Mechanism of tolerance induction

Clonal deletion:

Functionally immature cells of a clone

encountering antigen undergo a programmedcell death, as auto-reactive T-cells areeliminated in the thymus following interaction

with self antigen during their differentiation(negative selection).


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Clonal deletion:

Likewise, differentiating early B cells becometolerant when they encounter cell-associatedor soluble self antigen.

Clonal deletion has been shown to occuralso in the periphery.


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Clonal anergy:

Auto-reactive T cells, when exposed toantigenic peptides which do not possess co-stimulatory molecules (B7-1 or B7-2),become anergic to the antigen.


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Clonal anergy:

Also, B cells when exposed to large amountsof soluble antigen down regulate theirsurface IgM and become anergic. Thesecells also up-regulate the Fasmolecules ontheir surface. An interaction of these B cells

with Fas-ligand-bearing cells results in theirdeath via apoptosis.


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Receptor editing:

B cells which encounter large amounts ofsoluble antigen, as they do in the body, andbind to this antigen with very low affinitybecome activated to re-express their RAG-1and RAG-2 genes.

These genes cause them to undergo DNA

recombination and change their antigenspecificity.


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What are RAG-1 RAG-2?

Recombination signal sequences(RAG).

RAG-1 is a specific endonuclease and is

only active when complexed with RAG-2. Specific DNA sequences (heptamers)

found adjacent to the V, D, and J

segments in the antigen receptor loci andrecognized by the RAG-1/RAG-2component of the V(D)J recombinase.(see figure 7-11)


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RAG-1/RAG-2


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Anti-idiotype antibody: Anti-idiotype antibodies produced experimentally

have been demonstrated to inhibit immuneresponse to specific antigens.

Anti-idiotype antibodies are produced during theprocess of tolerization.

Such antibodies may respond to the uniquereceptors of other lymphocytes and serve to shut

off antigen specific responses. Therefore, these antibodies prevent the receptor

from combining with antigen.


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Termination of tolerance

Experimentally induced tolerance can beterminated by prolonged absence of exposure to

the tolerogen, by treatments which severelydamage the immune system (x-irradiation) or byimmunization with cross reactive antigens.

These observations are of significance in theconceptualization of autoimmune diseases.


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Dendritic cells: regulators of alloimmunity and

opportunities for tolerance induction

Dendritic cells (DCs) are uniquely well-equipped antigen-presenting cells (APCs)regarded classically as sentinels of the

immune response, which induce andregulate T-cell reactivity.

They play critical roles in central tolerance

and in the maintenance of peripheraltolerance in the normal steady state.


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Regulatory T cells


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Suppressor cells:

Both low and high doses of antigen mayinduce suppressor T cells (Regulatory Tcells) which can specifically suppressimmune responses of both B and T cells,either directly or by production of

cytokines, most importantly, TGF-b and IL-10.


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Regulatory T cells

CD4+ T lymphocytes that express highlevels of IL-2r a chain (CD25) but not othermarkers of activation.

Regulatory T cells may be generated byself antigen recognition in the thymus or inthe periphery.

These cells induce immunosuppression bysecreting TGF-b and IL-10 and therebyinhibit Mf function and IFN-g activity.


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Fig 10-10


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Oral tolerance

The gastrointestinal tract is the largestimmunologic organ in the body.

It is constantly bombarded by a myriad of dietaryproteins.

Despite the extent of protein exposure, very fewpatients have food allergies because ofdevelopment of oral tolerance to these antigens.

Once proteins contact the intestinal surface, theyare sampled by different cells and, depending ontheir characteristics, result in different responses.


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Oral tolerance


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T regulatory cell family

The idea of specific suppressor T cellpopulations that counteract harmfulautoaggressive immune responses in the

periphery was first described in the 1970sby Gershon et al.

However, at that time neither the cells northe hypothetical soluble suppressor factorsresponsible for the observed effects couldbe identified.


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In 1995 Sakaguchi et al. described for thefirst time a subpopulation of CD4+ T helper

cells, characterized by a constitutiveexpression of the IL-2 receptor a-chain(CD25), that is essential to control

autoaggressive immune responses in mice.


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After subsequent in vitro studies by severalgroups, this population is now referred to asCD4+CD25+ T regulatory cells (Tregs).

This distinct T cell population was originallydescribed in mice. However, comparable Tcell suppressor populations, with identicalphenotype and functional activities havebeen defined more recently in rats andhumans.


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They represent 5

10% of all peripheral

CD4+ T cells.

Freshly isolated CD25+ Tregs do not

proliferate after allogeneic or polyclonalactivation in vitro, but Tregs suppress theactivation and cytokine release of CD4+ andCD8+ T cells in an antigen-nonspecific andcell contact-dependent manner.


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However, it should be mentioned that theactivation of Tregs is also antigen-specific.

The main mechanism of suppression

seems to be the inhibition of IL-2transcription in the responder T cellpopulation.

Nevertheless, the molecules involved in thiscell contact-dependent suppression are stilllargely unknown.


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In the human immune system, two distinctsubsets of resident CD25+ Tregs can bedistinguished based on the expression of distinctintegrins.

Tregs expressing the a4b7 integrin can convertCD4+ T cells into IL-10-producing Tr1-like cells,whereas a4b1+ Tregs induce TGF-b -producingTh3-like cells.

The integrins a4b1 and a4b7 are homingreceptors for cellular migration of T lymphocytesto inflamed tissues and to mucosal sites,respectively.


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The a4b1-integrin binds to VCAM1 (vascular celladhesion molecule-1), which is induced on theendothelium of inflamed tissues, whereas thea4b7-integrin binds to vascular addressins,selectively expressed by venules in mucosaltissues.

Therefore, it can be postulated that a4b1+CD25+

Tregs migrate in vivoto inflamed tissues wherethey can inhibit effector T cell responses.

a4b7+CD25+ Tregs are specialized to migrate to

mucosal tissues, to counteract autoreactive Tcells, thereby preventing chronic mucosal

inflammations.


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History of Tolerance


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History of Tolerance

Timing

Some 50 years ago Owen observed twotypes of non-identical twin cattle, thosethat had shared a hemopoietic system inuterowere tolerant of blood cells fromeach other and those who had not, were

not cross-tolerant.


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History

Burnet postulated that there was a temporalwindow of tolerance such that antigensencountered while the immune system wasimmature tolerized the relevant lymphocytes.

Medewar subsequently investigated the effectsof transferring hemopoietic cells fromhistoincompatible mice at different times afterbirth. He found that if the cells were transferred

in the first few days of life (but not later) therecipient mouse acquiredlifelong tolerance tothe antigens of the donor.


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History


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History

The Danger Hypothesis

Matzinger versus Medewar?

Matzinger has proposed that there is not a

special window for tolerance duringneonatal life but that whether encounterwith an antigen results in tolerance or animmune response is determined by

whether the prevailing host environmentpromotes a response via nonspecific cues'sensing' danger.


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History

Polly has further suggested that the controlleddeath process of apoptosis is critical inpreventing autoimmunity when old or surplus

cells are disposed. The notion that the normal, default pathway of

the immune system is tolerance rather thanresponse is not a new idea to immunologists -

antigens usually fail to elicit a response unlessgiven with adjuvants, whose purpose is probablyto generate stimulatory cues (cytokines).


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History

Polly has further suggested that the controlleddeath process of apoptosis is critical inpreventing autoimmunity when old or surplus

cells are disposed. The notion that the normal, default pathway of

the immune system is tolerance rather thanresponse is not a new idea to immunologists -

antigens usually fail to elicit a response unlessgiven with adjuvants, whose purpose is probablyto generate stimulatory cues (cytokines).


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History

Recent experiments have shown that notonly can adults be tolerize under certaincircumstances, but that neonates can

make effective immune responses if theantigen is presented in sufficientlyimmunogenic form.


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History

I believe that the supposed conflict betweenMatzinger and Medewar is rather 'hyped up' andessentially a matter of detail.

Neonatal T cells are not intrinsically tolerizablebut the systemic neonatal environment doespredispose to tolerance.

Nevertheless, I think that her hypothesis hasdrawn the attention of a wider audience tocurrent ideas about tolerance induction and thefactors determining immune responsiveness.

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No 13 Immunological Tolerance