Th17 and Treg in RA

Seong Wook KangDivision of Rheumatology

Department of Internal MedicineChnungnam National University School of

Medicine

Rheumatoid Arthritis

Rheumatoid Arthritis (RA)

• A symmetric polyarticular arthritis • Primarily affects the small joints of

the hands and feet• Inflammation in the synovium • Pannus invades and destroys local

articular structures

Normal Synovium

Pathogenesis of RA

Role of T cells in RA

• Prominent T-cell infiltrate in RA synovium

• Genetic similarities between RA patients – specific human leukocyte antigen (HLA)-DR genes -

HLA DR4, DR14 and DR1

• Shared epitope – the third hypervariable region of DR β chains, espe-

cially amino acids 70 through 74

HLA Class II Molecule

antigen

HLA class II molecule

Antigen presenting cell

T cell

Maturation of lympho-cytes

Routes of antigen entry

Activation of naive and effector T cells by antigen

from thymus

Phases of T cell responses

Activated T cells deliver signals back to the APCs, further enhancing their ability to activate T cells

SIGNALS FOR T LYMPHOCYTE ACTIVATION

• Proliferation of T lymphocytes and differentiation into effector and memory cells require– Antigen recognition– Costimulation – Cytokines that are produced by the T cells themselves and by

APCs and other cells

Differentiation of CD4+ T Cells into TH1, TH2, and TH17 Effector Cells

Old versus new models of Th cell development

Th17 cells

• A novel lineage of CD4+ effector T helper (Th) cells which produce IL-17– Murine models of autoimmunity: experimental au-

toimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA)

• Mediated by Th1 response (?): ablated by Ab for IL-12p40

• IL-23 shares with IL-12p40– IL-12: p40 and p35

– IL-23: p40 and p19

• IL-23, not IL-12 is critically linked to autoimmunity in these models

• IL-23 polarized cells express genes associated chronic in-flammation, such as IL-17A, IL-17F, IL-6, TNF-a, and proin-flammatory chemokines

Main activities attributed to Th17 cells

Diseases associated with Th17

Possible role of Th17 cells in RA

• IL-17 and IL-23p19 were found in sera, synovial

fluid, and synovial biopsies of most patients with RA

• Increased expression of CC chemokine ligand 20 in

the inflamed joints of patients with RA– CCL20 : able to bind CCR6 expressing Th17 cells

• Increased number of Th17 cells were observed in

the peripheral blood and the SF of RA patients

Role of Th17 cells in RA

Helper T cell (Th) subgroups

Autoimmunity and Tolerance

• Breakdown of self-tolerance: autoimmune disease– T cell compartment of the immune system can react with a variety of antigens

• Equipped with receptors that are able to interact with self–antigens

• Auto-reactive T cell: potentially dangerous by initiating autoimmune responses

• Protective immune responses need to be stopped or down-regulated– When the body-invading agent has been neutralized

– Intensity or chronicity may become dangerous for the body

• Regulatory mechanisms are required

– Thymic clonal deletion: apoptotic cell death (central tolerance)

– Induction of anergy: functional inactivation

– Activation-induced cell death

– Suppression by regulatory lymphocytes: Role of FOXP3+ regulatory T cells (Treg)

T cells suppressing immune re-sponses

• Described early 1970s by Gershon and Kondo

• In mid-1990s, Sakaguchi identified a subset of CD4+

CD25+ T cells critical for preventing autoimmunity

– when CD4+ T cells depleted of CD25+ T cells from normal

mice were transferred into syngeneic athymic nude mice,

multiorgan autoimmune disease was induced

– Prevented by co-transfer of CD4+ CD25+ T cells

Sakaguchi S. J Immunol 1995

Discovery of FOXP3

• FOXP3 (forkhead family transcription factor)

– A critical regulator of Treg development, function, and

homeostasis

• FOXP3+ T cells, most of which are CD4+ CD25+

– suppress activation, proliferation and effector functions of im-

mune cells including CD4+ and CD8+ T cells, NK cells, NKT cells, B

cells and APCs

– central in the prevention of autoimmune disease, allergy, and

maintenance of allograft tolerance

FOXP3+ regulatory T cells in hu-man immune system

• Treg expressing FOXP3 are indispensable for the mainte-

nance of self tolerance and immune homeostasis

• Genetic mutations in FOXP3 develop a severe, fatal sys-

temic autoimmune disorder

– IPEX (Immune dysregulation Polyendocrinopathy Enteropathy

X-linked) syndrome

• Enlargement of lymphoid organ, insulin-dependent diabetes,

eczema, food allergy and concomitant infection

Regulatory T cells

• Many cell types have been shown to possess the ca-

pacity to regulate immune responses

– CD4+CD25high regulatory T cells (“Tregs”), CD4+ Tr1 cells, CD4+

Th3 cells, CD8+CD28− T cells, CD4−CD8− T cells and NKT cells

Characteristics of regulatory T cells

Natural regulatory T cells (nTreg) vs. In-duced Treg (iTreg)

• Natural regulatory T cells (nTreg): Thymic-derived

– One of the best-characterized subsets of immune regu-

latory cells is the CD4+CD25+/high Tregs

– FOXP3 appears to have emerged as the definitive

marker for such Tregs

• Induced Treg (iTreg)

– More recent studies have shown that FOXP3 may also be induced in CD4+FOXP3– T cells in vivo during some immune responses

Thymic and Peripheral Generation of FOXP3+ Treg Cells

Mechanisms of FOXP3+ Treg cell mediated suppression (direct)

Mechanisms of FOXP3+ Treg cell mediated suppression (indirect)

Tregs in autoimmune dis-eases

• No difference in the frequency of CD4+ CD25+ Tregs but re-

duced suppressive activity

– Multiple sclerosis

– Myasthenia gravis

– Type 1 diabetes

– Rheumatoid arthritis

• Decrease in CD4+ CD25+ Tregs frequency in peripheral blood

– SLE

– Kawasaki disease

– Autoimmune lymphoproliferative syndrome

Tregs in human RA

• Tregs in patients with RA appear to be present in normal num-

bers and to exhibit all of the features of Tregs, not only in phe-

notype but also in their suppression of T cell proliferation.

• Circulating Tregs isolated from patients with active RA are un-

able to suppress the release of pro-inflammatory cytokines by

activated T cells and monocytes

• Reversal of Treg-suppressive defect by successful anti-TNF

treatment

Tregs and inflammation in RA

• The frequency of Tregs was much greater in the synovial

fluid than in peripheral blood

– The inflammatory milieu increases the number of Treg cells in

the inflamed joint, but impairs their function

– TNFα in SF of RA abrogate the suppressive activity of

CD4+CD25+ Tregs

• Balance between Tregs and pathogenic Th17 cells at the site

of inflammation

– TGFβ and IL-6 secretion in rheumatoid synovium

Reciprocal generation of Treg and Th17 cells

Tregs can convert to Th17 cells

• Treg and Th17 cells may differentiate from the

same precursor T cells

– The balance of TGFβ and IL-6 might determine the

differentiation of Treg / Th17 cells

• The propensity of Tregs to convert to Th17 cells

in the context of pro-inflammatory stimuli

– FOXP3+CD4+ T cells can express RORγt and has the

capacity to produce IL-17

Balance between Th17 and Treg

Therapeutic potential of Tregs

• In vivo expansion of CD4+CD25+ Tregs

– Anti-CD3 monoclonal Ab (type I DM)

– CD28 superagonist

• Ex vivo generation of CD4+CD25+ Tregs

– Adoptive cell Therapy

Clinical applications of Tregs Adoptive cell Therapy

Cellular therapy in RA

• Tregs may convert to pathogenic cells in

human RA

• Strategies for expansion and isolation of

highly pure FOXP3+ Tregs to be used in cellu-

lar therapy

Summary• A role for Th17 in RA

– Inflammation

– Cartilage destruction

– Bone erosion

• Tregs have a key role in immune homeostasis

– Important functions in suppressing unwanted inflammatory responses

toward self-antigens

• Great potential to use these cells in a therapeutic regimen

for the treatment of autoimmune diseases