NEUROVASCULAR MEDICINE - Pursuing Cellular Longevity for Healthy Aging Part 7 ppsx

348 ELUCIDATING INFLAMMATORY MEDIATORS OF DISEASE

Table 14.1 Regulatory T-cell Populations

Cell Type Generation/Location Markers Properties and Function References

Natural Tregs Generated in the

thymus, predominantly

located in lymphoid

organs, migrate toward

sites of infl ammation

CD4, CD25, Foxp3,

CD45RBlow, CD62L,

CTLA-4 or CD152,

GITR, ±CD127,

±CD38

Antigen specifi c, secrete IL-10

and/or TGF-β, suppressive

activity, inhibit effector T-cell

functions, contact dependent,

require CD80 and CD86

ligands on target T cells

Hsieh et al. 2004; Fontenot,

Rudensky 2005; Ziegler 2006;

Scalzo et al. 2006

Inducible or

adaptive Tregs:

(1) Tr1

(2) Th3

Generated in the

periphery, migrate

toward sites of

infl ammation

CD4, CD25,

CD45RO

Target APC and T cells;

prevent autoimmune colitis

and infl ammation of the

digestive track mainly the gut,

and are mainly involved in

oral tolerance

Groux et al. 1997; Graca

et al. 2002; Chen et al. 2003;

Apostolou et al. 2004; Cottrez,

Groux 2004

Tr1 From naive CD4 T cells

in the presence of IL-10

and IFN-α

Secrete mainly IL-10, but

also TGF-β, IL-5, and IFN-γ;

do not secrete IL-2 or IL-4;

inhibit Th1 and Th2 cell

responses, regulate both naive

and memory T cells, inhibit

T-cell-mediated responses to

pathogens and alloantigens

and cancer; target APC

Groux et al. 1997; Foussat et al.

2003; Roncarolo et al. 2003;

Scalzo et al. 2006

Th3 Through oral antigen

administration

Produce mainly TGF- β but

also IL-10; suppress APC and

T-cells, mainly Th2

Weiner 1997; Scalzo et al. 2006

T helper 1 cells

(Th1)

Generated in the

periphery from Th0 or

Th2 cells mainly in the

presence of IL-12

CD4, CD25,

STAT-4, T-bet

Produce IL-2, IFN-γ,

lymphotoxin-α; target Th2

cells; activate phagocytosis,

opsonization, and comple￾ment protection against

intracellular antigens; respon￾sible for autoimmunity and

infl ammation

Mosmann, Coffman 1989; Boom

et al. 1990; Le Gros et al. 1990;

Romagnani 1991, 1994, 1997;

Hsieh et al. 1993

T helper 2 cells

(Th2)

Generated in the

periphery from Th0

cells or Th1 mainly in

the presence of IL-4

CD4, CD25,

STAT-6, GATA-3,

c-maf

Secrete IL-4, IL-5, IL-9, IL-13;

target Th1 cells; induce B-cell

function and eosinophil acti￾vation; participate in allergic

disorders

Abbas et al. 1996; Annunziato

et al. 2001; Smits et al. 2001;

Ghoreschi et al. 2003; Szabo

et al. 2003; Skapenko et al. 2004;

Scalzo et al. 2006

T helper 17

cells (Th17)

Generated in the periph￾ery from naive T cells

mainly in the absence

of IFN-γ, IL-4, and IL-6

and in the presence of

IL-β or TNF-α; IL-23

promotes their survival

CD4 Secrete IL-17A, F, IL-6, TNF-α,

IL-22; protect against extracel￾lular microbes, responsible

for autoimmune disorders,

infl ammation, downregulate

Treg function

Ye et al. 2001; Murphy et al. 2003;

Nakae et al. 2003; Langrish

et al. 2005; Bettelli et al. 2006;

Harrington et al. 2006; Iwakura,

Ishigame 2006; Liang et al. 2006;

Reinhardt et al. 2006; Tato,

O’Shea 2006; Annunziato

et al. 2007

CD8 regulatory

T cells

Generated in the thymus

and also in the periph￾ery (?), predominantly

located in lymphoid

organs, migrate toward

sites of infl ammation

CD8, Foxp3,

CD28−

, γδ

subgroup

Induction of tolerance; inhibit

T cells; antigen-specifi c (MHC

class Ib APC-dependent) sub￾group and IFN-γ-secreting,

nonantigen-specifi c subgroup;

CD8gdT cells secrete IFN-γ

and IL-4 and inhibit APC and

Th cells

Jiang et al. 1992; Hu et al. 2004;

Scalzo et al. 2006

Natural Killer

T cells (NKT)

Periphery CD3, CD56 Secrete IFN-γ and IL-4;

inhibit Th1/Th2 responses

and DCs; tolerogenic but also

proinfl ammatory in different

pathological conditions

Boyson et al. 2002; Scalzo et al.

2006; Godfrey, Berzins 2007;

Novak et al. 2007; Nowak,

Stein-Streilein 2007

APC, antigen presenting cell; DC, dendritic cell; IL, interleukin; IFN, interferon; TGF, transforming growth factor; (?), not clear.

Chapter 14: Immunomodulation: Role of T Regulatory Cells 349

suppressive potential that are not able to accumulate

and proliferate in the lymph nodes cannot suppress

or prevent disease (Tang, Henriksen, Bi et al. 2004;

Tarbell, Yamazaki, Olson et al. 2004; Jaeckel, von

Boehmer, Manns 2005). Therefore, it seems that in

vivo homing and proliferation of Tregs in the lymph

nodes are important for these cells to exert their sup￾pressive activity in the early phase of the immune

response. The migration of Tregs toward sites of

infl ammation is essential for their suppression of

T effector cells, and it has been shown that activated

Tregs change their homing receptors to accomplish

this task (Huehn, Siegmund, Lehmann et al. 2004).

It has also been demonstrated that natural Tregs are

predominantly located in lymphoid organs, whereas

another group of Tregs, Tr1 cells, tends to migrate

toward sites of infl ammation (Graca, Cobbold,

Waldmann 2002; Cottrez, Groux 2004).

Antigen exposure is very important for Tregs to

initiate suppressive activity. Interestingly, in vitro stud￾ies have also shown that activated Tregs can inhibit

the immune response, regardless of the antigen that

causes it (Thornton, Shevach 2000). Furthermore,

there is strong evidence that Foxp3-transduced CD4+

T cells specifi c for the OVA antigen are able to pro￾tect OVA-specifi c TCR-transgenic mice from GVHD

(Albert, Liu, Anasetti et al. 2005). There seems to be

antigen specifi city during the activation phase and a

bystander suppression phenomenon in the effector

suppressor phase.

Although the exact suppression mechanism

remains largely unknown, in vitro and in vivo research

has shown a relative contribution of both cell-to-cell

contact and soluble cytokine mechanisms. Accessory

molecules such as CTLA-4 and its ligands CD80,

CD86, and GITR, which are expressed on the surface

of Tregs, have been implicated (Takahashi, Kuniyasu,

Toda et al. 1998; Takahashi, Tagami, Yamazaki et al.

2000; Suri-Payer, Cantor 2001; Piccirillo, Letterio,

Thornton et al. 2002; Shimizu, Yamazaki, Takahashi

et al. 2002). In the GVHD murine model, CD4+CD25+

or CD4+CD25– T cells were unable to inhibit the devel￾opment of disease caused by effector T cells defi cient

in CD80 or CD86 ligands, indicating that suppression

of T-cell activation functions through CD80 and CD86

molecules on activated T cells and CTLA-4 on Tregs

(Paust, Lu, McCarty et al. 2004). Furthermore, stud￾ies have implicated cell surface TGF-β1 in the immu￾nosuppressive effect of Tregs (Nakamura, Kitani,

Strober 2001).

Inducible or Adaptive Tregs

Another important group of regulatory T cells includes

the T cells that can be induced by naive T cells in the

periphery under low doses of antigenic stimulation or

has also been detected in activated CD4+CD25+ cells

with no regulatory action (Seidel, Ernst, Printz et al.

2006).

CD127 (IL-7 receptor α chain) has been shown to

have a reverse relationship with the suppressive func￾tion of CD4+ Foxp3 T cells and is downregulated in

human T cells after activation. Cells separated on the

basis of CD4 and CD127 expression were shown to be

anergic and to possess suppressive action compared to

CD4+CD25+ T cells (Huster, Busch, Schiemann et al.

2004; Fuller, Hildeman, Sabbaj et al. 2005; Boettler,

Panther, Bengsch et al. 2006; Liu et al. 2006a; Seddiki,

Santner-Nanan, Martinson et al. 2006). Natural Tregs

develop in the thymus after positive selection on cor￾tical medullary epithelial cells (Bensinger, Bandeira,

Jordan et al. 2001). The selection of CD4+CD25+ thy￾mocytes requires an intermediate affi nity of TCRs for

self-peptides, since thymocytes with low-affi nity TCRs

do not yet undergo selection (Jordan, Boesteanu,

Reed et al. 2001). However, a defect in this selection

process contributes to the enrichment of autoreac￾tive Tregs, as these precursors seem to be resistant

to clonal deletion (van Santen, Benoist, Mathis et al.

2004; Romagnoli, Hudrisier, van Meerwijk 2005).

Nevertheless, this enrichment could be due to both

positive selection by self-ligands and the absence of

negative selection.

Antigen specifi city is required for natural Treg

activation. Studies with TCR-transgenic mice specifi c

for ovalbumin (OVA) have shown that protection

from graft-versus-host-disease (GVHD) is realized

only when the host T cells used for immunization rec￾ognize the antigen (Albert, Liu, Anasetti et al. 2005).

Tregs also recognize pathogen antigens. Tregs from

mice infected with Schistosoma or Leishmania produce

IL-10 in response to the same parasite antigens but

not other pathogens (Belkaid, Piccirillo, Mendez et al.

2002; Hesse, Piccirillo, Belkaid et al. 2004). In human

studies of asymptomatic human immunodefi ciency

virus–infected individuals, CD4+CD25+ peripheral

blood Tregs showed immunosuppressive properties

in an antigen-specifi c way (Kinter, Hennessey, Bell

et al. 2004). The same phenomenon was observed in

Helicobacter pylori–infected patients (Raghavan, Suri￾Payer, Holmgren 2004).

The in vivo suppressive activity of Tregs requires

close contact with T effectors with certain antigen

specifi city. Tregs seem to require strong localiza￾tion to parts of the body where antigenic stimulation

occurs, like draining lymph nodes. Furthermore, it

has been shown that suppression of activated T cells

occurs when the ratio of Tregs to T effectors is one

third. Since the percentage of Tregs is only 2 to 3% of

total T cells, selective homing, as well as expansion, is

very important for a suppressive effect to be achieved.

It has been shown in animal models that cells with

350 ELUCIDATING INFLAMMATORY MEDIATORS OF DISEASE

Furthermore, desmoglein 3–specifi c Tr1 cell induc￾tion requires the presence of IL-2; these cells function

mainly through IL-10 and TGF-β secretion, indicating

their critical involvement in tolerance homeostasis in

response to the specifi c antigen (Beissert, Schwarz,

Schwarz 2006).

TH3 It has been shown in an experimental allergic/

autoimmune encephalomyelitis (EAE) model that the

oral delivery of myelin basic protein (MBP) antigen

generates a T-cell population that inhibits the infl am￾matory reaction. This population was identifi ed as the

Th3 cell subgroup of T regulatory cells and produces

high amounts of TGF-β and moderate amounts of

IL-10, and has the ability to inhibit the development

of autoimmunity (Weiner 1997). Anti-TGF-β monoclo￾nal antibodies inhibit the suppressive effects of Th3

cells, indicating the importance of TGF-β in immu￾nosuppression through Th3 cells. Th3 cells have been

shown to inhibit the proliferation and cytokine pro￾duction of MBP-specifi c Th1 clones through TGF-β.

This suppression is antigen nonspecifi c and is medi￾ated through TGF-β, indicating a bystander suppres￾sion–based mechanism (Weiner 1997). Furthermore,

suppression of Th2, as well as Th2 clones, by Th3 cells

has also been demonstrated, suggesting a unique role

for this orally induced Treg population.

Th1 and Th2 Regulation

For the last 20 years, the classical concept of the

immune response included two main branches of

the T-cell group, Th1 and Th2 cells, based mainly on

the type of cytokines produced. Th1 cells were found

to produce IL-2, IFN-γ, and lymphotoxin-α, and Th2

cells were found to produce IL-4, IL-5, IL-9, and IL-13

(Mosmann, Coffman 1989; Romagnani 1991). These

two cell groups also differ in the transcription factors

used for their regulation. Th1 cells are regulated by

transcription factors that include STAT-4 and T-bet,

whereas Th2 development is regulated by factors

such as STAT-6, GATA-3, and c-maf, which are also

antagonistic to the transcription factors belonging to

the Th1 branch (Hsieh, Macatonia, Tripp et al. 1993;

Szabo, Sullivan, Peng et al. 2003). Th1 transcription

factors STAT-4 and T-bet are usually activated in the

presence of IL-12 or IFN-γ. IL-12 is produced by den￾dritic cells and IFN-γ is produced by NK cells when

activation by highly conserved microbial products

occurs. Th2 transcription factors are activated when

IL-4, instead of IL-12 or IFN-γ, is present (Le Gros,

Ben-Sasson, Seder et al. 1990). Cytokines produced

by Th1 cells activate phagocytosis, opsonization, and

complement protection against intracellular parasites,

whereas Th2 cytokines induce mainly B-cell function

and eosinophil activation (Romagnani 1994; Abbas,

in the presence of immunosuppressive cytokines like

TGF-β (Chen, Jin, Hardegen et al. 2003; Apostolou

von Boehmer 2004; von Boehmer 2005). There are

two subgroups of inducible Tregs, Tr1 and Th3, and

they cannot be separated on the basis of their pheno￾type. In addition, they are better characterized on the

basis of the cytokines they use as mediators. Tr1 and

Th3 cells are similar—Tr1 cells are characterized by

their large amount of IL-10 secretion and their role

in preventing autoimmune colitis (Groux, O’Garra,

Bigler et al. 1997) and Th3 cells play an important

role in oral tolerance through the secretion of TGF-β

(Chen, Kuchroo, Inobe et al. 1994). None of these sub￾groups expresses Foxp3, and the suppression effect

on Th1 and Th2 cells mediated by TGF-β1 and IL-10

is MHC unrestricted and antigen nonspecifi c (Vieira,

Christensen, Minaee et al. 2004).

TR1 Tr1 cells were fi rst identifi ed in a murine model

in which CD4+ transgenic T cells generated Tr1 cells

after repetitive stimulation by their cognate peptide

in the presence of IL-10 (Groux O’Garra, Bigler et al.

1997). Tr1 cells are characterized by the secretion

of large amounts of IL-10 and moderate amounts of

TGF-β, IL-5, and interferon γ (IFN-γ). These cells

do not secrete IL-2 or IL-4 (Groux O’Garra, Bigler

et al. 1997). Although they show poor proliferative

ability after polyclonal or antigen-specifi c stimula￾tion, they can inhibit T-cell responses in vitro and in

vivo through mechanisms similar to bystander sup￾pression, as has been shown in the case of colitis. Tr1

cells are capable of regulating the activation of naive

and memory T cells and also inhibit T-cell–mediated

responses to pathogens and alloantigens, as well as

cancer (Foussat, Cottrez, Brun et al. 2003; Roncarolo,

Gregori, Levings 2003). Neutralizing anti-IL-10 anti￾bodies blocks most of the immunosuppressive effects

of Tr1, demonstrating the importance of IL-10 in Tr1’s

immunosuppressive function (Roncarolo, Bacchetta,

Bordignon et al. 2001). It has also been shown that

complement can play a role in Tr1 induction. Resting

CD4+ T cells treated with anti-CD3 and anti-CD46

antibodies in the presence of IL-2 resulted in the

induction of Tr1 cells. CD46 is an important comple￾ment regulator that induces Tr1 through an endoge￾nous receptor–mediated event (Kemper, Chan, Green

et al. 2003). Tr1 cells have been shown to be important

in controlling autoimmunity. In the case of pemphigus

vulgaris, desmoglein 3–specifi c Tr1 cells maintained

and restored natural tolerance against the pemphigus

vulgaris antigen (Veldman, Hohne, Dieckmann et al.

2004). Healthy individuals carrying the pemphigus￾associated human leukocyte antigen (HLA) class II

allele DRB1*0402 and DQB1*0503 were found to have

desmoglein 3–responsive Tr1 cells that secreted IL-10

although these cells were rarely found in patients.

Chapter 14: Immunomodulation: Role of T Regulatory Cells 351

by lack of T-bet (Harrington, Mangan, Weaver 2006).

Furthermore, TGF-β secreted from Tregs in the pres￾ence of IL-6 was responsible for the differentiation of

Th17 cells, and IL-1β or TNF-α addition signifi cantly

increased the percentage of naïve T cells that differ￾entiated into Th17. The presence of IL-23 seems to be

important for the maintenance and survival of Th17

cells, although it was not necessary for their genera￾tion (Reinhardt, Kang, Liang et al. 2006).

Th17 cells are induced through the production

of IL-23 from dendritic cells and are involved in the

pathogenesis of infl ammatory and autoimmune dis￾eases such as rheumatoid arthritis, systemic lupus

erythematosus, and EAE (Murphy, Langrish, Chen

et al. 2003; Nakae, Nambu, Sudo et al. 2003; Langrish,

Chen, Blumenschein et al. 2005). Th17 cells produce

IL-17 and IL-22, which is a member of the IL-10 family

(Ye, Rodriguez, Kanaly et al. 2001; Tato, O’Shea 2006;

Liang, Tan, Luxenberg et al. 2006). These cytokines

induce fi broblasts and endothelial and epithelial

cells, as well as macrophages, to produce chemok￾ines that result in the recruitment of polymorphonu￾clear leukocytes and the induction of infl ammation

(Ye, Rodriguez, Kanaly et al. 2001). Thus, IL-17 may

play a protective role against extracellular bacteria,

although, under certain circumstances, infl ammation

is induced by macrophages through the production

of IL-1, IL-6, and metalloproteinases (Cua, Sherlock,

Chen et al. 2003; Park, Li, Yang et al. 2005). Th17 cells

do not express Th1 or Th2 transcription factors such

as T-bet or GATA-3 (Dong 2006). Therefore, clarifi ca￾tion of the pathogenetic role of Th17 cells may provide

more information on the role of other Th cell groups

in protecting against different pathogens. Murine

model experiments have suggested that Th17 cells are

involved in autoimmune phenomena like infl amma￾tory bowel disease and EAE. Th17 originate through

the production of IL-23 by dendritic cells, which has

been shown to be due to the combined activity of IL-6

and TGF-β. TGF-β is also involved in the generation of

Tregs. Furthermore, there is evidence for a functional

antagonism between Th17 and Foxp3 Tregs (Bettelli,

Carrier, Gao et al. 2006). Since the production of

Th17 cells is inhibited by IL-6, IL-4, and IFN-γ, there

must be a regulatory point that separates the genera￾tion of Th17 cells, which are pathogenic and induce

autoimmunity, from Foxp3 Tregs, which inhibit auto￾immunity (Iwakura, Ishigame 2006).

CD8+ and NK T cells (or NKT cells)

CD8+ T cells have also been shown to possess immuno￾suppressive activity; this also results in the inhibition

of EAE (Jiang, Zhang, Pernis 1992) by inhibiting Th1

encephalitogenic cells. These CD8+ T cells exert their

suppressive activity only after being primed during

Murphy, Sher et al. 1996). Currently, the Th1 branch

is considered to be mainly responsible for phenomena

such as autoimmunity, whereas the Th2 branch par￾ticipates in allergic disorders (Romagnani 1997). A

process known as immune deviation refl ects the mutual

regulation between the Th1 and Th2 responses. The

presence of IL-12, IL-18, IFN-γ, and IFN-α induces

the development of Th1 cells while at the same time

inhibiting the development of Th2 cells. Microbial

products induce the secretion of IL-12 and IFNs,

leading Th2 responses toward a Th0 or Th1 type

of response (Maggi, Parronchi, Manetti et al. 1992;

Parronchi, De Carli, Manetti et al. 1992; Manetti,

Parronchi, Giudizi et al. 1993; Kips, Brusselle, Joos

et al. 1996; Lack, Bradley, Hamelmann et al. 1996; Li,

Chopra, Chou et al. 1996). The presence of IL-12 is

important in the polarization of immune responses,

since it can shift even established Th2 responses

toward a Th1 response (Annunziato, Cosmi, Manetti

et al. 2001; Smits, van Rietschoten, Hilkens et al. 2001).

On the other hand, the presence of IL-4 inhibits Th1-

cell type development and can in turn shift established

Th1 responses toward a Th2 phenotype, although the

opposite phenomenon can occur just as easily (Boom,

Liebster, Abbas et al. 1990; Ghoreschi, Thomas, Breit

et al. 2003; Skapenko, Niedobitek, Kalden et al. 2004).

Furthermore, some chemokines can interact with Th1

or Th2 cells and shift their balance in either direc￾tion, thus inducing the production of certain cytok￾ines (Karpus, Lujacs, Kennedy et al. 1997).

Th17: Treg Antagonists?

Beyond the initially polarized forms of Th effector

T cells (Th1 and Th2, as well as Th0 CD4+ cells),

another subset has been identifi ed. This subset, called

Th17, is distinct from Th1, Th2, and Th0 cells. Th17

cells secrete IL-17A, IL-17F, IL-6, and tumor necrosis

factor α (TNF-α.) cytokines.

Th17 cells are protective against extracellular

microbes but also seem to be responsible for auto￾immune disorders in mice (Annunziato, Cosmi,

Santarlasci et al. 2007). Recent studies show that

these cells are probably a separate lineage of Th

cells and that they do not represent just another Th1

population that has undergone further differentia￾tion (Harrington, Mangan, Weaver 2006; Reinhardt,

Kang, Liang et al. 2006). When naive CD4+ T cells

were cultured in the presence of anti-IFN-γ mono￾clonal antibody, induction of Th17 population was

observed. This observation was stronger with IL-4

inhibition, which is an indication of Th17 inhibi￾tion in the presence of IFN-γ and IL-4 (Reinhardt,

Kang, Liang et al. 2006). The T-bet transcription fac￾tor seems to play an important role in Th1 cell dif￾ferentiation, but Th17 cell growth is not infl uenced

352 ELUCIDATING INFLAMMATORY MEDIATORS OF DISEASE

function of autoreactive cells or a decrease in the

function of regulatory mechanisms, leading to auto￾immunity. However, a decrease in these regulatory

mechanisms can lead to immunodefi ciency.

Autoimmunity targeting the nervous system has

been studied extensively in animal models and human

subjects (Mouzaki, Tselios, Papathanassopoulos et al.

2004; Mouzaki, Deraos, Chatzantoni 2005; Owens,

Babcock, Millward et al. 2005; Boscolo, Passoni,

Baldas et al. 2006; Alaedini, Okamoto, Briani et al.

2007; Cabanlit, Wills, Goines et al. 2007; Cassan,

Liblau 2007; Correa, Maccioni, Rivero et al. 2007;

Krishnamoorthy, Holz, Wekerle 2007; Tschernatsch,

Gross, Kneifel et al. 2007; Weber, Prod’homme,

Youssef et al. 2007) and a plethora of experimental and

clinical observations indicate that all major types of

immune cells together with cells of the central nervous

system (CNS) are involved in the resulting damage to

the nervous system mediated through direct cell-to￾cell cytotoxicity and/or soluble mediators that include

cytokines, chemokines, and antibodies (Table 14.2).

In the following paragraph immunomodulation

in the nervous system in relation to T-cell regulation

will be analytically discussed with the use of multiple

sclerosis (MS) as a prototype autoimmune disease of

the nervous system (Toy 2006).

Immunomodulation in the Nervous System:

The Paradigm of Multiple Sclerosis

MS is considered to be a chronic autoimmune demy￾elinating disease that results in axonal loss within the

CNS.

MS is characterized by T cell and macrophage

infi ltrates that are triggered by CNS-specifi c CD4

the fi rst episode of EAE. There are indications that

these cells function through the nonclassical MHC

class Ib pathway, since their suppressive function can

be blocked by MHC class Ib Qa-1 antibodies. Qa-1 cells

have the ability to present foreign and self-peptides to

CD8+ T cells (Hu, Ikizawa, Lu et al. 2004).

NK T cells are innate cells that can be induced to

secrete both proinfl ammatory and anti-infl ammatory

cytokines immediately on exposure to activating sig￾nals and induced to regulate an ongoing immune

response, usually in conjunction with other regu￾latory T-cell types. NK T cells recognize glycolipid

antigens presented by a monomorphic glycoprotein

CD1d. Numerous works have shown that NK T cells

may serve as regulatory cells in autoimmune diseases

and are tolerogenic in conditions of prolonged expo￾sure to foreign antigen (e.g., in pregnancy) (Boyson,

Rybalov, Koopman et al. 2002). However, recent stud￾ies have revealed that the presence of NK T cells accel￾erates some infl ammatory conditions, implying that

their protective role against autoimmunity is not pre￾determined (Godfrey, Berzins 2007; Novak, Griseri,

Beaudoin et al. 2007; Nowak, Stein-Streilein 2007).

AUTOIMMUNITY AND T REGULATION

On the basis of what has been previously reported in

this chapter, immune tolerance as a whole is the result

of a very sensitive balance between naturally arising

autoreactive cells and the regulatory mechanisms

that regulate these autoreactive processes. In terms

of immune regulation as discussed so far, autoimmu￾nity can be considered to be manifested by a loss of

balance among these functions. This lack of balance

can result from either an increase in the number or

Table 14.2 Immune Disorders that Affect the Nervous System

Immune Disorder Implicated Cell Types Mediators References

Leukocyte recruitment to the

CNS, axon terminal degeneration,

hippocampal lesions, MS, EAE

CD4, CD8 T cells, NK

cells, B cells, CD45CD11b

MΦ, microglia

IFN-γ, TNF-α, IL-1β, Abs,

chemokine MCP-1/CCL2

expression by blood–brain

barrier– associated glial cells

Mouzaki et al. 2004; Owens et al.

2005; Toy 2006; Cassan, Liblau 2007

MS, EAE, reduced suppressive

activity of Tregs

Th1 and Th17 cells

recognizing MBP, PLP,

MOG self-peptides

IFN-γ, TNF-α, IL-17 Mouzaki et al. 2004, 2005; Langrish

et al. 2005; Haas et al. 2005; Huan

et al. 2005; Bettelli et al. 2006;

Cassan, Liblau 2007

Infl ammation, Alzheimer’s disease,

MS, viral or bacterial infections,

ischemia, stroke, encephalopathy

Brain/hypothalamus Agonists: IL-1β, IFN-γ

Antagonists: IL-4, TGF-β

Toy 2006; Correa et al. 2007

Myasthenia gravis, Lambert—

Eaton myasthenic syndrome,

Guillain—Barre syndrome,

paraneoplastic cerebellar degener￾ation, generalized neuropathies

B cells Antibrain Abs, antigliadin

Abs, Abs to glial antigens

Boscolo et al. 2006; Alaedini

et al. 2007; Cabanlit et al. 2007;

Tschernatsch et al. 2007

CNS, central nervous system; MS, multiple sclerosis; EAE, experimentally induced autoimmune encephalomyelitis; MΦ, macrophage;

Ab, antibody.

Chapter 14: Immunomodulation: Role of T Regulatory Cells 353

organ system for the induction of immune responses

based on the following facts:

• The limited renewal and mitotic nature of neurons

protect the CNS from immune pathology.

• The blood–brain barrier does not allow traffi cking

of resting lymphocytes, whereas it does allow the

entrance of activated cells (Hickey, Hsu, Kimura

1991).

• The fact that only a few cells within the CNS consti￾tutively express MHC molecules makes it diffi cult

for immune responses to develop (Perry 1998).

• A functional silencing or elimination of T cells

that manage to enter the CNS occurs through the

expression of CNS Fas-ligand, TGF-β, and prosta￾glandin E2 (Zhu, Anderson, Schubart et al. 2005;

Liu, Teige, Birnir et al. 2006b).

Nevertheless, recent evidence has proved that

there is access to the CNS, although limited, and naive

T cells have been shown to traffi c within the infl amed

tissue (Krakowski, Owens 2000; Aloisi, Pujol-Borrell

2006). Studies in animal models have also shown that

naive CD4+ and CD8+ T cells are able to patrol nonlym￾phoid tissues including the CNS (Brabb, von Dassow,

Ordonez et al. 2000; Cose, Brammer, Khanna et al.

2006). Although these cells are allowed to circulate

T cells. The prominent autoimmune etiology of MS

is considered to be the aberrant activation of IFN￾γ-producing Th1 cells that recognize self-peptides

of the myelin sheath, such as MBP, proteolipid pro￾tein (PLP), and myelin oligodendrocyte glycoprotein

(MOG) (Mouzaki, Tselios, Papathanassopoulos et al.

2004).

There is a heterogeneous pathophysiology of this

disease that remains unclear and includes an infl am￾matory response characterized by CD4+ CD8+ T cells

and macrophages. MBP, PLP, and MOG components

of the myelin sheath are the main specifi c targets of

T cells and B cells that are directed against these self￾peptides (Olsson, Sun, Hillert et al. 1992; Genain,

Cannella, Hauser et al. 1999; Bielekova, Goodwin,

Richert et al. 2000; Berger, Rubner, Schautzer et al.

2003; Bielekova, Sung, Kadom et al. 2004; Sospedra,

Martin 2005). The etiology for the immune system,

triggering such an infl ammatory response against

self-antigens of the CNS, remains largely unknown,

similar to most autoimmune diseases.

The proposed mechanism for the pathophysiol￾ogy of this disease based on what we know so far is

described in Figure 14.2 and Table 14.3.

Our knowledge of CNS dynamics and function so

far gives the impression that the CNS is a privileged

Figure 14.2 Treg implication in multiple sclerosis pathogenesis. BBB, blood brain barrier; CNS, central nervous system; MΦ, macrophage;

APC, antigen presenting cell; IFN, interferon; TNF, tumor necrosis factor.

Periphery

T cells return

to circulation

Induction of autoreactive

T-cell invasion

Crossing of the BBB

through diapedesis

Peripheral

activation

by

infectious

or other

factors

Autoreactive T cells that

have escaped central or

peripheral tolerance

Autoantigen

presentation by an

APC within the CNS

Anergy

IL-1, IL-4, IL-10

Activation

proliferation

Epitope spreading

Release of new

CNS

‘‘sequestered’’

antigens

Inflammatory

environment

CNS

injury

B-cell and

complement

activation

CNS

3

1

2

CTLA-4

costimulation

costimulation

CD28

Cytokine

production

IF N-γ

TNF-α

M

activation

IFN-γ

TNF-α

Central tolerance failure/T autoreactive toward Treg shift failure

3 Treg-reduced suppressive activity

1

2