2. The regulatory T-cells (Tregs) were formerly
known as suppressor T-cells.
They are a subpopulation of T-cells that modulate
the immune system, maintain tolerance to self-
antigens and prevent autoimmune disease.
This is an important “self-check” built into the
immune system to prevent excessive reactions.
3. Tregs suppress activation of the immune system
and prevent pathological self-reactivity i.e.
autoimmunity.
The molecular mechanism by which Tregs exert
their suppressor/ regulatory activity has not been
defined accurately.
The immunosuppressive cytokines TFG-ß and IL-
10 have been implicated in the Treg cells function.
4. Another control mechanism is through the IL-2
feedback loop.
Antigen-activated T-cells produce IL-2 which then
act on IL-2 receptors on Tregs alerting them of the
fact that high T-cell activity is occurring, and
thereby mount a suppressory response against
them.
Negative feedback loop to ensure that over-
reaction is not occurring.
5.
6. Like helper T-cells, the Tregs display the CD4
antigen on their surface.
However, the Tregs are distinguished by their
additional display of the CD25 surface antigen
and their expression of a transciption factor,
termed FOXP3 (forkhead box P3), that
programs their development.
7. Under the influence of TGF-ß, Treg cells mature
from CD4+ precursors.
They acquire the expression of markers typical
of Tregs like:
• CD25
• CTLA-4 (cytotoxic T-lymphocyte associated molecule-
4)
• GITR (glucocorticoid-induced TNF receptor)
Upon up-regulation of the transcription factor
FOXP3, Treg cells begin their suppressive
effect.
8. Natural Tregs :
• CD4+CD25+ T-cells
• develop and emigrate from the thymus
• play an important role in immune homeostasis
Adaptive Tregs :
• CD4+ T-cells
• acquire CD25 expression outside of the thymus
(defining distinction)
• induced by inflammation, autoimmunity and cancer
9. The various suppression mechanisms used by
Treg cells can be grouped into four basic modes
of action:
• Suppression by inhibitory cytokines
• Suppression by cytolysis
• Suppression by metabolic disruption
• Suppression by modulation of dentric cell
maturation or function.
10. Inhibitory cytokines like IL-10 and TGF-ß act as
mediators of Treg-cell induced suppression.
Recently, a new inhibitory cytokine, IL-35 has
been described that is preferentially expressed by
Treg cells.
Limit the anti-tumor activity of effector T-cells.
11.
12. Cytolysis mediated through secretion of granzymes is
considered as the forte of natural killer cells and CD8+
cytotoxic T-cells.
Consistent with this, nTregs have been shown to
express granzyme A and granzyme B, and suppress NK
and cytotoxic T-cells by killing them in a granzyme- and
perforin-dependent mannner.
Activated Tregs induce apoptosis of effector T-cells
through a TRAIL-DR5 pathway (Tumor-necrosis-factor
Related Apoptosis-Inducing Ligand – Death Receptor
5).
13.
14. High expression level of CD25 empowers Treg
cells to consume local IL-2 and therefore starve
the actively dividing effector T-cells by depleting
the IL-2 they need to survive.
Cytokine (IL-2)-deprivation mediated apoptosis
15. Concordant expression of ectoenzymes CD39 and
CD73 generates pericellular adenosine, that
suppresses effector T-cell function through
activation of adenosine receptor 2A (A2AR).
Binding of adenosine to the receptor also enhance
the generation of induced Tregs by promoting
TGF-ß and inhibiting IL-6.
Tregs suppress effector T-cells by directly
tranferring the inhibitory cAMP into effector T-cells
through membrane gap junctions.
16.
17. Tregs modulate the maturation and function of
DCs which are required for the activation of
effector T-cells.
Mediated by CTLA-4 expressed by Tregs
Interactions between CTLA-4 and CD80 / CD86
induces production of IDO (indoleamine
dioxygenase), resulting in suppression of effector
T-cells.
18. Tregs may also decrease the capacity of DCs to
activate effector T-cells.
Lymphocyte-activation gene 3 (LAG3) may block
DC maturation.
19.
20. However, systemic depletion of Treg cells may
elicit deleterious autoimmunity.
Mutations of the gene encoding the Treg-specific
transcription factor FOXP3 impair Treg cell
development and cause a fatal multi-organ
autoimmune disease called IPEX syndrome
(immunodysregulation, polyendocrinopathy and
enteropathy, X-linked syndrome)
21. Characterised by development of overwhelming
systemic autoimmunity in the first year of life,
resulting in the triad of watery diarrhoea,
eczematous dermatitis and endocrinopathy, seen
as insulin-dependent diabetes mellitus.
Males are affected, while females are carriers
Coombs-positive hemolytic anemia, autoimmune
thrombocytopenia, autoimmune neutropenia and
tubular nephropathy.
The majority of patients die within the first year of
life of either metabolic derangements or sepsis.
22. Most tumors elicit an immune response in the host
that is mediated by tumor antigens.
This causes large number of tumor-infiltrating
lymphocytes (TILs) to be found in the tumor
microenvironment.
Tregs seem to be preferentially trafficked to the
tumor microenvironment.
Tregs not only suppress autoimmunity, they also
suppress host’s immune defense against the
tumor antigens.
23. In normal individuals, the Tregs represent only 5
to 10% of the population of CD4+ lymphocytes,
the remainder being helper T cells.
In cancer patients, this number may increase to
25 to 30%.
Infiltration of a large number of Treg cells into
tumor tissues is often associated with poor
prognosis.
24. Several innate and adaptive immune cells
participate in the recognition and destruction of
cancer cells – known as cancer
immunosurveillance.
Highly immunogenic cancer cell clones are
eliminated in immunocompetent hosts.
However, cancer cells avoid such
immunosurveillance through the outgrowth of
weakly immunogenic cancer cells – a process
known as immunoediting/ immunoevasion.
25. Escape from immune attack is an important step
in the progression of tumors toward the malignant
growth state.
Immunoevasion has been recognised as a
hallmark of cancer.
Tregs are the major components that facilitate
tumor immune escape.
26.
27. In humans, tumors in the head and neck, breast,
lung, liver, gastrointestinal tract, pancreas and
ovary have been shown to harbor a large number
of tumor-infiltrating Treg cells.
Decreased ratios of tumor-infiltrating CD8+ T-cells
to FOXP3+ Treg cells were shown to correlate
with poor prognosis.
This indicates that Tregs suppress effector T-cells
and hinder the body’s immune response against
cancer.
28. However, the opposite is true in some cancers and
high levels of Tregs are associated with a positive
prognosis.
This is seen in colorectal carcinoma and follicular
lymphoma.
These opposite effects indicate that Tregs role in
development of cancer is dependent on both type
and location of tumor.
29. Although FOXP3 appears to be required for
human Treg cell development and function,
expression of FOXP3 alone is not sufficient for
regulatory function.
Consequently, FOXP3 is not an adequate marker
for human Treg cells.
There is great interest in identifying cell surface
markers that are uniquely and specifically
expressed on all FOXP3 expressing Tregs,
however till date no such molecule has been
identified.
30. Recent advances in cancer immunotherapy target
Tregs suggest that molecules relatively specific to
Treg cells are good candidates for Treg depletion
or functional modulation.
These molecules include CTLA-4, GITR, CCR4,
PD-1, OX-40 and LAG3.
31. Anti-CTLA4-antibody, also known as checkpoint
blockade therapy.
Two fully humanized monoclonal antibody against
CTLA-4 (Ipilimumab and Tremelimumab) have
been tested in patients with melanoma, prostate
cancer and RCC.
They target Treg cells which are abundant in
tumor tissues and express high levels of CTLA-4.
32. Surface molecules expressed specifically or
selectively on effector Tregs are good targets.
CCR4 is predominantly expressed by effector
Tregs, not by naive Tregs and helper T-cells.
Treg migration and infiltration into various tumor
tissues appear to be dependent on the expression
of CCR4 ligands (CCL22).
33. Use of anti-CCR4 antibody has been shown to
be effective in depleting effector Tregs
selectively and augmenting induction of tumor-
specific CD4+ and CD8+ T-cells.
34. GITR is another molecule expressed by Tregs and
can serve as a target for functional modulation.
The antibody for GITR is under clinical trials for
use in melanoma and other advanced solid
tumors.
Antibodies specific for other molecules such as
OX40 are under clinical investigation.
35. The A2AR antagonists are currently undergoing
cancer clinical trials.
IDO inhibitors have also entered clinical trials in
combination with immune checkpoint blockade.
36. It is hoped that the combination of Treg-cell
targeting (by reducing Tregs or attenuating their
suppressive activity in tumor tissues) with the
activation of tumor-specific effector T-cells (by
cancer vaccine or immune checkpoint blockade)
will make the current cancer immunotherapy more
effective.