th17 and treg in ra seong wook kang division of rheumatology department of internal medicine...

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