Download Regulatory T cells and autoimmune diseases

Th17 and Treg in RA
Seong Wook Kang
Division of Rheumatology
Department of Internal Medicine
Chnungnam 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, especially
amino acids 70 through 74
HLA Class II Molecule
T cell
antigen
HLA class II molecule
Antigen presenting cell
Maturation of lymphocytes
Routes of antigen entry
Activation of naive and effector T cells by antigen
from thymus
Activated T cells deliver signals back to the APCs,
further enhancing their ability to activate T cells
Phases of T cell responses
 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
autoimmune encephalomyelitis (EAE) and collageninduced 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
inflammation, such as IL-17A, IL-17F, IL-6, TNF-a, and
proinflammatory 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 responses
• 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 immune
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 human
immune system
• Treg expressing FOXP3 are indispensable for the maintenance of
self tolerance and immune homeostasis
• Genetic mutations in FOXP3 develop a severe, fatal systemic
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
capacity 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.
Induced Treg (iTreg)
• Natural regulatory T cells (nTreg): Thymic-derived
– One of the best-characterized subsets of immune
regulatory 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 diseases
• No difference in the frequency of CD4+ CD25+ Tregs but reduced
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 numbers
and to exhibit all of the features of Tregs, not only in phenotype
but also in their suppression of T cell proliferation.
• Circulating Tregs isolated from patients with active RA are unable
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 cellular
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