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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