T Regulatory Cells in Allergy

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Molecular mechanisms in allergy and clinical immunology

Series editors: William T. Shearer, MD, PhD, Lanny J. Rosenwasser, MD, and Bruce S. Bochner,MD

T regulatory cells in allergy: Novel concepts inthe pathogenesis, prevention, and treatmentof allergic diseases

Mubeccel Akdis, MD, PhD, Kurt Blaser, PhD, and Cezmi A. Akdis, MD Davos, Switzerland

This activity is available for CME credit. See page 32A for important information.

The identification of Tregulatory (TReg) cells as key regulators of

immunologic processes in peripheral tolerance to allergens has

opened an important era in the prevention and treatment of

allergic diseases. Both naturally occurring CD41CD251 TReg

cells and inducible populations of allergen-specific IL-10–

secreting TR1 cells inhibit allergen-specific effector cells in

experimental models. Allergen-specific TReg cell responses

contribute to the control of allergic inflammation in several

ways. Skewing of allergen-specific effector T cells to a TReg

phenotype appears to be a crucial event in the development of

a healthy immune response to allergens and successful outcome

in allergen-specific immunotherapy. The increased levels of

IL-10 and TGF-b produced by TReg cells can potently suppress

IgE production while simultaneously increasing the production

of the noninflammatory antibody isotypes IgG4 and IgA,

respectively. TReg cells directly or indirectly suppress effector

cells of allergic inflammation, such as mast cells, basophils, and

eosinophils, and contribute to remodeling in asthma and atopic

dermatitis. In addition, mediators of allergic inflammation that

trigger cyclic AMP–associated G protein–coupled receptors,

such as histamine receptor 2, might play a role in peripheral

tolerance mechanisms against allergens. Current strategies for

drug development and allergen-specific immunotherapy

exploit these observations with the potential to provide cure for

allergic diseases. (J Allergy Clin Immunol 2005;116:961-8.)

Key words: T regulatory cells, immunotherapy, tolerance, anergy,IgE, T cells, histamine, IL-10, TGF-b

The initial event responsible for the development ofallergic diseases is the generation of allergen-specificCD41 TH cells.1 Once generated, effector TH2 cells

From the Swiss Institute of Allergy and Asthma Research (SIAF).

The authors’ laboratories are supported by Swiss National Foundation grants

32-100266, 31-65436, and 32-105268 and the Global Allergy and

Asthma European Network (GA2LEN).

Received for publication May 3, 2005; revised September 2, 2005; accepted

for publication September 7, 2005.

Available online October 10, 2005.

Reprint requests: Cezmi A. Akdis, MD, Swiss Institute of Allergy and Asthma

Research (SIAF), Obere Strasse 22, CH7270 Davos, Switzerland. E-mail:

[email protected].

0091-6749/$30.00

� 2005 American Academy of Allergy, Asthma and Immunology

doi:10.1016/j.jaci.2005.09.004

produce IL-4, IL-5, IL-9, and IL-13 and mediate severalregulatory and effector functions. These cytokines inducethe production of allergen-specific IgE by B cells, devel-opment and recruitment of eosinophils, production of mu-cus, and contraction of smooth muscles.1 TH1 cells mightalso efficiently contribute to the effector phase in allergicdiseases2,3 or dampen allergic inflammation, dependingon specific disease model and stage of the inflammation.4

In addition to TH1 and TH2 cells, a further subtype ofT cells with immunosuppressive function and cytokineprofiles distinct from either TH1 or TH2 cells is termedregulatory-suppressor T cells (TReg cells, Fig 1).5-8 TReg

cells are able to inhibit the development of allergic TH2responses and play a major role in allergen SIT.8,9 Subsetsof TReg cells with distinct phenotypes and mechanisms ofaction include the naturally occurring, thymus-selectedCD41CD251FoxP31 TReg cells and the inducible type 1TReg cells (TR1 cells).10,11 In addition, subsets of CD81

T cells, gd T cells, dendritic cells (DCs), IL-10–producingB cells, natural killer cells, and resident tissue cells, whichmight promote the generation of TReg cells, could contrib-ute to suppressive and regulatory events.11 During the lastfew years, the concept of TReg cells has received generalattention by the scientific community, and excitementabout the possibility of these cells in therapeutic applica-tions for the treatment of diseases that are associatedwith a dysfunction in T-cell regulation has been aug-mented. As discussed in this review, understanding theimmune mechanisms that prevent disease occurrence innonallergic individuals and evidence for healing of alteredregulatory mechanisms in allergic diseases offers promisefor new immune interventions (Table I).

Abbreviations usedCTLA4: Cytotoxic T lymphocyte–associated antigen 4

DC: Dendritic cell

HR: Histamine receptor

SIT: Specific immunotherapy

TReg cell: T regulatory cell

TR1: T regulatory type 1

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mailto:[email protected]

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962 Akdis, Blaser, and Akdis

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MECHANISMS OF TReg CELL GENERATION

DCs not only control immunity but also maintainperipheral tolerance, 2 complementary functions thatwould ensure the integrity of the organism in an environ-ment full of pathogens and allergens. The tolerogenicfunction of DCs depends on certain maturation stages andsubsets of different ontogenies and can be influenced byimmunomodulatory agents. The differentiation of thymus-derived TReg cells does not depend on the interactionwith specialized DCs,12 whereas a role for DCs in the in-duction of TR1 cells has been supported by several studies.Immature DCs control peripheral tolerance by inducingthe differentiation of TR1-like cells.

13 Related to the pre-vention and development of asthma, airway DCs controlthe pulmonary immune response and determine toleranceand immunity to newly encountered antigens. ImmatureDCs are distributed throughout the lungs and capture aller-gens and migrate to the T-cell area of mediastinal lymphnodes within 12 hours.14 They express a partially maturephenotype with an intermediate array of costimulatorymolecules and induce T-cell tolerance.15 Antigen presen-tation by partially mature airway DCs that express IL-10induce the formation of TR1-like cells, which inhibit sub-sequent inflammatory responses.16 Moreover, depletionand adoptive transfer of pulmonary plasmacytoid DCshas demonstrated an important role for these cells inprotection from allergen sensitization and asthma de-velopment in mice.17 Although molecular mechanismsof TReg cell generation remain to be elucidated, someexisting therapies for allergic diseases, such as treatmentwith glucocorticoids and b2-agonists, might function topromote the numbers and function of IL-10–secretingTR1-like cells.

18,19

FIG 1. The generation of allergen-specific TReg cell response is

an essential step in allergen SIT and natural allergen exposure of

nonallergic individuals. IL-10 and TGF-b secreted from TReg cells

directly or indirectly suppress TH2 cells, TH1 cells, mast cells,

eosinophils, and basophils and regulate antibody isotypes in

B cells. Red line, Suppression; black line, stimulation.

TReg CELLS IN HEALTHY IMMUNE RESPONSETO ALLERGENS

Studies on immune response to allergens in healthyindividuals demonstrated that a peripheral T-cell reper-toire to allergens exists that recognizes the same T-cellepitopes as allergic patients.20-22 Accordingly, activeregulation emerges as a very essential mechanism forboth inducing and maintaining peripheral tolerance toallergens. The analysis of T-cell subsets specific to variousfood or inhaled antigens enables a suitable human modelto investigate how harmless environmental proteins arerecognized and tolerated by the immune system. Singleallergen-specific T cells constitute less than 0.1% of thewhole CD41 T-cell repertoire and can be isolated fromthe peripheral blood of human subjects according totheir cytokine profile.22 Freshly purified IFN-g–, IL-4–,and IL-10–producing allergen-specific CD41 T cells dis-play characteristics of TH1, TH2, and IL-10–secreting TReg

cells (TR1–like cells), respectively.22 Specific TR1 cellsconsistently represent the dominant subset against com-mon environmental allergens in healthy individuals, incontrast to the high frequency of allergen-specific IL-4–secreting T cells in allergic individuals. TR1 cells can actby secreting cytokines, such as IL-10 and TGF-b, butcontact-dependent signals, such as programmed death-1,glucocorticoid-induced TNF receptor, membrane TGF-b,and cytotoxic T lymphocyte–associated antigen 4(CTLA4), appear to be important in some situations.10,22

Healthy and allergic individuals exhibit all 3 allergen-specific subsets in different proportions, indicating that achange in dominant subset might lead to allergy develop-ment or recovery. The ratio between specific TR1 andTH2 cells determines the development of a healthy or an

TABLE I. Definitions of anergy, tolerance, suppression,

and ignorance

Anergy: Clinically, anergy describes the lack of T cell–dependent,

cutaneous, delayed-type hypersensitivity reactions to common

antigens. Lymphocyte anergy is the failure of T- or B-cell clones

to react to antigenic stimulation as a state of unresponsiveness.

Immunologic ignorance: Lack of immune response development

because of insufficient doses, stability, or inaccessibility of

antigen to the immune system.

Immune suppression: Suppression of the immune response by a

defined molecular mechanism.

Mucosal tolerance: A state of antigen-specific unresponsiveness

after mucosal exposure to antigens.

Suppressor T cell: T cells that block the activation and function

of other effector T lymphocytes, a function that can now be

attributed to TReg cells.

Inducible TReg cells: TR1 cells and other TReg subsets, which are

generated in the peripheral immune system.

Natural TReg cells: Thymus-derived, CD41CD251 TReg cells.

Tolerance: An induced state of antigen-specific immunologic

unresponsiveness by exposure to antigens in an immunocompetent

individual.


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allergic immune response. Although in low frequency, theexistence of potential suppressive allergen-specific TR1cells in allergic individuals suggests a possible methodof treatment.

TReg CELLS IN ALLERGEN SIT

Allergen SIT is most efficiently used in allergy to insectvenoms and allergic rhinitis.23,24 Despite its use in clinicalpractice for nearly a century, the underlying immunologicmechanisms are slowly being elucidated.11,23 IncreasedIgG4 isotype antibodies supposedly block IgE-facilitatedallergen presentation.25 A reduction in the numbers ofmast cells and eosinophils, including the release of medi-ators,26,27 is associated with successful allergen SIT.

It appears, however, that the induction of a tolerantstate in peripheral T cells represents an essential step inallergen SIT (Fig 1).8,9,28,29 Peripheral T-cell toleranceis characterized mainly by suppressed proliferative andcytokine responses against the major allergens and theirT cell–recognition sites.28 The generation of allergen-specific TReg cells and increased production of theirsuppressive cytokines IL-10 and TGF-b are essentialearly events in allergen SIT.8,9

Targeting pathogenic T cells with vaccines consistingof synthetic T-cell epitope peptides (peptide immunother-apy) is another attractive approach for investigation ofperipheral T-cell tolerance in human subjects. To date,clinical trials of peptide immunotherapy have beenperformed in 2 allergies.30-32 Induction of peripheral tole-rance directed to whole allergen and increases in IL-10have been reported.30-32 Complete allergens with fullT-cell repertoires are apparently necessary because multi-ple T-cell epitopes are recognized individually by differ-ent patients as a result of the large diversity of majorhistocompatibility antigens and T-cell receptors. Thegeneration of novel fusion proteins that combine majorallergens offers advantages over T cell peptide–basedimmunotherapy because these vaccines can be designedto comprise the complete repertoire of T-cell epitopeswithout binding IgE.33 As a promising model for otherallergies, single-dose administration of a hybrid vaccinethat combines 2 major allergens of bee venom, phospho-lipase A2 and hyaluronidase, prevents IgE developmenton exposure to native allergen in mice.33

TReg CELL RESPONSE TO ALLERGENS ISASSOCIATED WITH REGULATION OFANTIBODY ISOTYPES

How different subsets of TReg cells cross-talk to B cells,which leads to regulation of antibody production, is anessential question. CD41CD251CD692 TReg cells canmigrate to germinal centers and negatively regulate Tcell–dependent B-cell antibody production in mice.34 Inhumans the serum levels of specific IgE and IgG4 anti-bodies delineate allergic and normal immunity to aller-gen. Although peripheral tolerance was demonstrated in

specific T cells, the capacity of B cells to produce speci-fic IgE and IgG4 antibodies was not abolished duringallergen SIT.28 In fact, specific serum levels of both iso-types increased during the early phase of treatment.The increase in antigen-specific IgG4 levels was morepronounced, and the ratio of specific IgE to IgG4decreased by 10- to 100-fold. A similar change in specificisotype ratio was observed in SIT of various allergies.Moreover, IL-10, which is induced and increasingly se-creted by SIT, counterregulates antigen-specific IgE andIgG4 antibody synthesis.8 IL-10 is a potent suppressorof both total and allergen-specific IgE, whereas it simul-taneously increases IgG4 production.8 IL-10 has 2 majoreffects on B cells, which could result in the shift in bal-ance as observed. IL-10 decreases e transcript expressionand therefore production of IgE when added to PBMCsduring the first 3 days of culture. However, IL-10 inducesfurther upregulation of IgE production when added toalready committed B cells.35 Furthermore, IL-10 enhancesg4 transcript expression and IgG4 production induced byIL-4.35 Thus IL-10 not only generates tolerance in T cells,it also regulates specific isotype formation and skews thespecific response from an IgE- to an IgG4-dominated phe-notype (Fig 1). In healthy individuals antibody responseto Der p 1 is characterized by specific IgA and IgG4levels, small amounts of IgG1, and almost undetectableIgE antibodies in serum.9 House dust mite SIT did notsignificantly change specific IgE levels after 70 days oftreatment; however, a significant increase in specificIgA, IgG1, and IgG4 levels was observed.9 The increaseof specific IgA and IgG4 levels in serum coincides withincreased TGF-b and IL-10 levels, respectively.Although further studies are required, this might accountfor the role of IgA and TGF-b, as well as IgG4 andIL-10, in mucosal immune responses to allergens inhealthy individuals.8,36 These findings suggest a regula-tory function in addition to the well-known suppressorfunction of TReg cells.

TReg CELL RESPONSE TO ALLERGENS ISASSOCIATED WITH SUPPRESSION OFEFFECTOR CELLS

Despite the fact that a definite decrease in IgE antibodylevels and IgE-mediated skin sensitivity normally requiresseveral years of SIT, most patients are protected againstbee stings already at an early stage of bee venom SIT. Thereason for this is that effector cells of allergic inflamma-tion, such asmast cells, basophils, and eosinophils, requireT-cell cytokines for priming, survival, and activity,37

which are not efficiently provided by suppressed TH2cells (Fig 1). TReg cells generated by SIT might efficientlymodulate the thresholds for mast cell and basophil acti-vation and decrease IgE-mediated histamine release.38,39 Inaddition, IL-10 reduces proinflammatory cytokine releasefrom mast cells,40 downregulates eosinophil function andactivity, and suppresses IL-5 production by human restingTH0 and TH2 cells.41 Development of IgE response to


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helminths has been commonly observed, although thereis no typically accompanying allergic diseases. IL-10–producing B cells were suggested as an underlyingmechanism for the prevention of anaphylaxis duringSchistosoma mansoni infection, suggesting the controlof mast cell degranulation threshold by IL-10.42

Helminth infections are also accompanied by high levelsof helminth-specific IgG4 as a link for IL-10, peripheraltolerance, and suppression of allergic reactions.43

HISTAMINE RECEPTOR 2 AS A KEY PLAYERIN PERIPHERAL TOLERANCE

Many established G protein–coupled receptor systemshave been successfully exploited by the pharmaceuticalindustry to become the target for approximately 40% of thecurrently available drugs.44 As a small-molecular-weightmonoamine that binds to 4 different G protein–coupledreceptors, histamine has been demonstrated to regulateseveral essential events in the immune response.45,46

The expression of these receptors on different cells andcell subsets is regulated, and apparently diverse effectsof histamine on immune regulation are due to differentialexpression of these receptors and their distinct intracellu-lar signals. Histamine receptor (HR) 2 is coupled to aden-ylate cyclase, and studies in different species and severalhuman cells demonstrated that inhibition of characteristicfeatures of the cells by primarily cyclic AMP formationdominates in HR2-dependent effects of histamine.47

Histamine actively participates in the function andactivity of DC precursors, as well as their immature andmature forms. In the differentiation process of DCs frommonocytes, HR1, HR3, and HR4 act as positive stimuli

FIG 2. Suppressive functions of histamine by HR2. HR2 is highly

expressed on TH2 cells and negatively regulates T-cell proliferation

and IL-4 and IL-13 production. T cells are more efficiently sup-

pressed by TGF-b in the presence of histamine through HR2. HR1

on TH1 cells enhances IFN-g and proliferation and increases effec-

tor functions and tissue injury. Red line, Suppression; black line,

differentiation. APC, Antigen-presenting cell.

that increase antigen-presentation capacity, proinflam-matory cytokine production, and TH1 priming activity.In contrast, HR2 acts as a suppressive molecule for anti-gen-presentation capacity, suppresses IL-12 production,enhances IL-10 production, and induces IL-10–producingT cells (Fig 2).48,49

It has been demonstrated that differential patterns of HRexpression on TH1 and TH2 cells determine reciprocalT-cell responses after histamine stimulation.45 TH1 cellsshow predominant, but not exclusive, expression ofHR1, whereas TH2 cells show increased expression ofHR2. Histamine enhances TH1-type responses by trigger-ing HR1, whereas both TH1- and TH2-type responses arenegatively regulated by HR2.45 In mice deletion of HR1results in suppression of IFN-g and dominant secretionof TH2 cytokines (IL-4 and IL-13). HR2-deleted miceshow upregulation of both TH1 and TH2 cytokines. In ad-dition, increased IL-10 production in both DCs and T cellsthrough HR2 might account for an important regulatorymechanism in the control of allergen-specific T cellsthrough histamine.50 In accordance with this phenome-non, histamine supports the suppressive effect of TGF-bon particularly TH2 cells through HR2.51 Thus histamineand HR2 promote the development of peripheral toleranceduring SIT in several pathways. Histamine induces theproduction of IL-10 by DCs48 and TH2 cells and sup-presses both TH1 and TH2 cytokines.45,50 In addition,histamine enhances the suppressive activity of TGF-bon T cells (Fig 2).51 Whether this pathway is defectivein chronic allergic individuals and might act as a targetfor possible treatment modalities remains to be elucidated.Because of the same signal transduction patterns, b2-adrenergic receptors and some other G protein–coupledreceptors might function similarly to HR2 in humans.52

LINKS BETWEEN IMMUNOLOGICIGNORANCE, IMMUNE SUPPRESSION,ANERGY, AND TReg CELLS

Peripheral T-cell tolerance is characterized by func-tional inactivation of the cell to antigen encounter, whichremains alive for an extended period of time in anunresponsive state. The overall evaluation of the studieson T-cell unresponsiveness suggest that anergy, immuno-logic ignorance, and suppression are not entirely distinctbut rather represent linkedmechanisms possibly involvingthe same molecular events (Fig 3 and Table I).

TReg cells, mucosal IgA, andimmunologic ignorance

The mucosal surfaces of the respiratory, gastrointesti-nal, and urogenital tracts, covering a total of 300 m2 incontact with the external environment, represent majorsites of antigen exposure. Discriminating between patho-genic antigens, toward which a protective immuneresponse has to be established, and harmless antigens,such as food, airborne antigens, or the commensal bacte-rial flora that should be ignored, is the most challenging




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task of the mucosal immune system. Induction of mucosaltolerance or immunologic ignorance of harmless environ-mental proteins, as well as infectious agents, by secretoryIgA antibodies are 2 main mechanisms.53 The associationbetween serum and mucosal secretory IgA levels and thedevelopment of allergy has been recently questioned.Antigen-specific secretory IgA antibodies in the gutwere decreased in a mouse model of food allergy, suggest-ing a role for secretory IgA in peripheral tolerance tofoods. Peyer’s patch CD31 cells were primarily involvedby favoring IgA production through the release of IL-10and TGF-b, and low IL-10 production in Peyer’s patchesfavored the symptoms of food allergy.54 In another studyallergen-specific secretory IgA was found to protect sensi-tized children from allergic symptoms during the first 2years of life, suggesting a possible preventive role ofsecretory IgA against the development of allergy.55 Inaddition, increases in allergen-specific IgA levels havebeen reported in SITs performed through the sublingualor subcutaneous routes.9,56

TReg cells, remodeling in asthma, andimmunologic ignorance

Remodeling in asthma, which might be the conse-quence of excessive repair processes after repeated airwayinjury, includes increased deposition of several extracel-lular matrix proteins in the reticular basement membraneand bronchial mucosa, as well as increases in airwaysmooth muscle mass, goblet-cell hyperplasia, and newblood vessel formation.57 Consequently, the airway wallin asthma is usually characterized by increased thicknessand markedly and permanently reduced airway caliber.A major TReg cytokine, TGF-b, in particular, is a potentregulator of fibroblast and myofibroblast function andcontrols the production of several extracellular matrix pro-teins, including collagens, proteoglycans, and tenascin.58

Other cell types involved in allergic inflammation aspotential sources of TGF-b include eosinophils, macro-phages, mast cells, neutrophils, endothelial and epithelialcells, and smooth muscle cells and fibroblasts them-selves.58 TGF-b interacts with several other cytokines,such as activin for the efficiency of remodeling response.59

The thickening of the subepithelial lamina reticularisin bronchial asthma has been related to an increase infibroblasts in correlation with TGF-b expression.60 Sup-porting these findings, therapeutic treatment of mice withanti-TGF-b antibody significantly reduced peribron-chiolar extracellular matrix deposition, airway smoothmuscle cell proliferation, and mucus production in thelung.61 In some respects airway remodeling might repre-sent a continuum from inflammation to scarring, but itcould also be a protective response to altered airway im-munology caused by ongoing cellular activation and tissuedamage. There is clear evidence that lamina reticularisthickening starts very early, even at the time of first diag-nosis,62 suggesting that a barrier between activated epithe-lium or mucosal allergens and inner tissues (ie, immunesystem cells) occurs with the aim of downregulation ofthe allergen-induced inflammatory response.

Taken together, increased subepithelial lamina reticu-laris thickness and mucosal IgA production against aller-gens might be related to TReg cells, which attempt todecrease the amount of allergen exposure and play a rolein immunologic ignorance (Fig 3).

TReg cells and anergy: Active suppression ofT-cell costimulation by IL-10

The term anergy was first coined by Von Pirquet in1908 to describe the loss of delayed-type hypersensitivityto tuberculin in individuals infected with measles virus.63

The term has been clinically adopted to describe negative

FIG 3. Involvement of TReg cells in immunologic ignorance and

anergy. A, increased subepithelial lamina reticularis thickness

and mucosal IgA production might lead to immunologic ignorance

by decreasing the amount of allergen entrance to the submucosal

immune system cells in the lungs. B, IL-10 secreted from TReg cells

induces DCs to develop into IL-10–producing DCs and blocks T-cell

costimulation signals and leads to an anergic status.


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tuberculin skin test results in conditions in which theywere expected to be positive. In 1980, the term anergywas used to describe the specific inactivation of B cellsin mice by high doses of antigen.64 It was subsequentlyused for T cells to describe a phenomena in which antigenpresentation to T-cell clones in the absence of professionalantigen-presenting cells induced a hyporesponsive state,affecting subsequent IL-2 production and proliferationon restimulation.65 Inhibition of T-cell costimulatory mol-ecules at the cell surface or their intracellular signal trans-duction has been repeatedly reported to play an importantrole in T-cell unresponsiveness. The interaction betweenB7 and CD28 might determine whether a T-cell responsedevelops. Blocking antibodies to B7-2 inhibit the develop-ment of specific IgE, pulmonary eosinophilia, and airwayhyperresponsiveness in mice.66 CTLA4 seems to act onendogenous inhibitors of T-cell activation, and CTLA4-Ig, a soluble fusion protein, has also been effective inblocking airway hyperresponsiveness in mice.67 Further-more, cytokine production by memory-effector T cells,particularly those of the TH2 subset, is highly dependenton costimulation through the inducible costimulator/B7RP1(inducible costimulator ligand) pathway. Blockage68 orgenetic disruption69 of this costimulatory pathway mark-edly reduced allergen-induced asthma in mice, suggestinga promising approach for the treatment of allergic diseasein human subjects.

One mechanism of direct T-cell suppression by IL-10 isdue to the inhibition of CD28 costimulation (Fig 3). IL-10does not affect the proliferative responses of T cells thatwere stimulated with anti-CD3. In contrast, IL-10 signifi-cantly inhibits the anti-CD28–stimulated proliferation.70

Thus IL-10 suppresses only those T cells that have low

FIG 4. TReg cells contribute to the control of allergen-specific

immune responses in 5 major ways: (1) suppression of antigen-

presenting cells (APC) that support the generation of effector TH2

and TH1 cells; (2) suppression of TH2 and TH1 cells; (3) suppression

of allergen-specific IgE and induction of IgG4, IgA, or both; (4) sup-

pression of mast cells, basophils, and eosinophils; and (5) interac-

tion with resident tissue cells and remodeling.

numbers of T-cell receptors triggered and that requireCD28 for proliferation.70 Ligation of IL-10 receptor atthe time of CD28 stimulation inhibits tyrosine phospho-rylation of CD28.70 As a consecutive event for signaltransduction, the association of CD28 with the phosphati-dylinositol 3–kinase p85 molecule is inhibited by IL-10.Taken together, after a century of its first use, the term an-ergy is immunologically defined in the context of IL-10–secreting TR1 cells. Containment and cure of tuberculosisrequires an effective cell-mediated immune response, andits absence during severe forms of active tuberculosisinfection in parallel to tuberculin skin test negativity hasbeen demonstrated to be related to IL-10–mediatedperipheral tolerance.71 Accordingly, T-cell response inIL-10–mediated peripheral tolerance functions in thesame way as the original definition of anergy becausecostimulatory signals are suppressed, and T cells receivea weak signal only through the T-cell receptor withoutcostimulation (Fig 3).

CONCLUSION

Peripheral T-cell tolerance is a key immunologicmechanism in healthy immune response to self-antigensand noninfectious non–self-antigens. This phenomenon isclinically well documented in allergy, autoimmunity,transplantation, cancer, and infection. There is growingevidence supporting the role for TReg cells, immuno-suppressive cytokines, or both as a mechanism by whichallergen SIT and healthy immune response to allergensis mediated. TReg cells contribute to the control of allergen-specific immune responses in 5 major ways (Fig 4):(1) suppression of antigen-presenting cells that supportthe generation of effector TH2 and TH1 cells; (2) suppres-sion of TH2 and TH1 cells; (3) regulatory function on Bcells by suppression of allergen-specific IgE and inductionof IgG4, IgA, or both; (4) suppression of mast cells, baso-phils, and eosinophils; and (5) interaction with resident tis-sue cells and remodeling. In addition to the treatment ofestablished allergy, it is essential to consider prophylacticapproaches before initial sensitization has taken place.Preventive and therapeutic vaccines that induce TReg

responses can be developed. Allergen-specific TReg cellsmight in turn dampen both the TH1 and TH2 cells andcytokines, ensuring a well-balanced immune response.However, it has to be considered that TReg cells mightnot always be responsible for beneficial effects becauseseveral studies have shown that they could be responsiblefor the chronicity of infections and tumor tolerance. TReg

cell populations have proved possible but difficult togrow, expand, and clone in vitro. A crucial area for futurestudies is the identification of drugs, cytokines, or costi-mulatory molecules that induce in vivo growth whilepreserving the suppressor function of TReg cells.

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