AUTOIMMUNITY AND THE ROLE OF
T-REGULATORY CELLS
BY PRAGYA VATS
3015
GENETICS
Introduction to Autoimmune
Diseases
• The immune system has the ability to recognize one’s own antigen as “self” and thus does not mount
immune responses against them. This non reactivity against self antigen is called “self-tolerance”.
• Auto-immunity occur when the immune system mistakenly attacks the body’s own healthy cells
and tissues or antigens or a condition in which this tolerance is broken down .
• When this regulation fails, autoimmunity develops, causing chronic inflammation and tissue
damage.
There are over 80 autoimmune disorders known.
• Common examples include:
• ~Type 1 Diabetes: Immune attack on pancreatic β-cells.
~Rheumatoid Arthritis: Inflammation of the joints.
~Lupus: Affects multiple organs like skin, kidneys, and heart.
~Multiple Sclerosis: Immune damage to nerve coverings.
• Causes involve a mix of genetic, environmental, and hormonal factors.
• Overall,
autoimmune diseases highlight what happens when the body’s defense system turns
against itself .
THEORIES EXPLAINIG IMMUNOLOGICAL TOLERANCE
1. CLONAL DELETION THEORY
It was proposed by Burnet. This theory suggests that during
acquisition of immune competence , developing B and T cells that
acquire antigen specificity for self antigen are negatively selected i.e
the self reacting B and T cells undergo atopsis.
2. CLONAL ANERGY
When T and B cells do not get proper stimuli during antigen
recognition, they become non responsive to self antigen. This state
of non responsiveness is called anergy.
3. IDEOTYPIC NETWORK THEORY:
This is proposed by Neils Jerne. This theory suggests that in response
to antibody production, population of antibodies is also induced
which neutrilizes the self antibodies and participate in the process of
their clearance from the system.
The Discovery of Regulatory T Cells (Tregs)
The concept of specific immune cells dedicated to maintaining tolerance emerged in the 1990s, challenging the prevailing
understanding of immune activation. This led to the identification of a distinct CD4+CD25+ T cell subset that possessed potent
immunosuppressive capabilities. These cells, later termed Regulatory T cells (Tregs), were found to be essential for preventing
autoimmunity and maintaining immune homeostasis. Then a massive decline was observed in studies after which re - introduction
was done by Fujimoto.
Initial Identification FoxP3 as Master Regulator IPEX Syndrome Link
Identified as a distinct CD4+CD25+ T The FoxP3 transcription factor was Loss-of-function mutations in FoxP3
cell subset, essential for immune recognized as the master regulator, cause IPEX syndrome (Immune
tolerance and preventing self-attack. orchestrating Treg development and dysregulation, Polyendocrinopathy,
suppressive functions. Enteropathy, X-linked), a severe
By GERSHAN AND KONDO
autoimmune disorder, highlighting
Tregs’ critical role in preventing
widespread autoimmune attacks.
What Are T Regulatory Cells
(Tregs)?
IN PRIMARY LYMPHOID ORGAN while maturation, T cells
reacting to self antigen may have three fates:
- First they strongly reacts to the self antigen, it undergoes
apoptosis.
- Second, some survive apoptosis by modifying their
receptor specificity through a process called receptor
editing
- Third if the cells reacts with intermediate or low affinity, it
becomes natural regulaytory cells
1.A population of T-cells acquire regulatory role and do
not allow self reactive cells to mount effective response. The
role od Tregulatory cells is highly appreciated for maintaining
oral tolerance that prevents generation of response against
antigens taken as food through oral route.
{APPROXIMATELY 5-6%}
They are identified by markers such as CD4⁺,
CD25⁺, and the transcription factor FoxP3, essential
for their function.
Tregs release inhibitory cytokines like I L - 10 and
TGF-β to control other immune cells.
They maintain immune tolerance, preventing
the immune
system from attacking the body’s own tissues.
Proper Treg function ensures a healthy balance
between immune activation and suppression.
Key Treg Markers
Identifying and characterizing regulatory T cells relies on a specific set of molecular markers expressed on their surface or within their cytoplasm.
These markers are crucial for distinguishing Tregs from other T cell subsets and are often used in both diagnostic and therapeutic contexts.
FOXP3 (Forkhead box P3) CD4 & CD25
The definitive intracellular transcription factor for Treg development Tregs are primarily CD4+ T cells. High constitutive expression of
and function. Its expression is essential for their suppressive the interleukin-2 receptor alpha chain (CD25) is a classic marker,
activity. crucial for IL-2 signaling and Treg survival.
CTLA-4 (Cytotoxic T-lymphocyte-associated protein IL-10 & TGF-β
4)
Tregs secrete these key anti-inflammatory cytokines, which are
An inhibitory receptor expressed on Tregs that plays a vital role in critical for mediating their suppressive effects on effector T cells
their suppressive function by outcompeting CD28 for B7 ligands on and other immune cells.
antigen-presenting cells, thereby downregulating T cell activation.
CD
4+
There are two major types of Tregs:
Natural Tregs (nTregs): These "natural" Tregs develop in
the thymus during T cell maturation. They undergo
strong recognition of self-antigens, leading to their
differentiation into suppressive cells that express high
levels of FoxP3 early in their development. They are
crucial for maintaining central tolerance
Induced Tregs (iTregs): These arise from naïve T cells in
the periphery upon encountering antigens and help
control immune responses during inflammation or
infection as they escape the thymus.
The effect of microenvironment on differentiation of T
precursor cells into a specialized regulatory cell can be
seen in Mucosa associated lymphoid tissue (MALT).
High local concentration of TGF-B in malts supports
differentiation of T cells into T-regulatory cells that help
in maintaining tolerance.
IPEX Syndrome – Example of Treg Defect
• Full form: Immune dysregulation, Polyendocrinopathy,
Enteropathy, X-linked syndrome.
•Cause: Mutation in the FOXP3 gene, which is essential for
the
development and function of T regulatory cells (Tregs).
•Effect: Absence or severe dysfunction of Tregs → loss of immune
tolerance. Tregs are either absent or non-functional, resulting in a
total loss of immune tolerance. The disease begins early in infancy
and affects multiple organs
• Onset: Appears in infancy and affects multiple organs.
• Major symptoms:
~Type 1 diabetes (autoimmune destruction of β-cells)
~Severe chronic diarrhea (autoimmune enteropathy)
~Eczema and skin inflammation
~Thyroid or other endocrine disorders
• Significance:
~Demonstrates that functional FOXP3⁺ Tregs are essential
for preventing autoimmunity.
~Studied as a model disease for developing Treg-
Mechanism of Action of T
Regulatory Cells
(Tregs):
Secretion of inhibitory cytokines:
Tregs release cytokines like I L- 10 and TGF-β,
which
suppress excessive immune responses and
promote [Link] produce cytokines,
downs regulation of MHC II and co APCs.
Direct cell-to-cell suppression:
They inhibit T helper (Th1, Th17) and
cytotoxic T cells through physical contact,
preventing unwanted immune attacks.
Metabolic disruption:
Tregs consume I L- 2, a key growth factor for
T cells,
thereby limiting the activation and
proliferation of other immune cells.
Regulation of antigen-presenting cells
(APCs): They reduce the ability of APCs to
present antigens and produce inflammatory
BY KILLING CELLS
BY STARVING
BY CYTOKINE
SECRETION
Tregs in a Healthy Person
Functions of Tregs in a Healthy Body:
Maintain self-tolerance: Prevent the
immune system from attacking the
body’s own cells and tissues, reducing
the risk of autoimmunity.
Control immune response:
Regulate the strength of the immune
reaction during infections to avoid
excessive inflammation or tissue
damage.
Restore balance after infection: Once
the infection is cleared, Tregs suppress
unnecessary immune activity and bring
the system back to its resting state.
Maintain immune homeostasis:
Ensure a stable balance between
Tregs in Autoimmune Diseases
When T regulatory cells (Tregs) are defective, reduced in number, or lose their
suppressive ability, the immune system fails to maintain self-tolerance. This
breakdown of immune regulation plays a crucial role in the development of
autoimmune diseases.
Loss of Immune Tolerance:
Without effective Tregs, the immune system can no longer distinguish between self
and non-self antigens.
Activation of Auto-reactive Cells:
Self-reactive T and B cells escape regulation and become abnormally activated,
producing harmful antibodies and inflammatory cytokines.
Chronic Inflammation:
Persistent immune activation leads to long-term inflammation in various tissues and
organs.
Tissue Damage:
Continuous immune attack results in destruction of healthy tissues, leading to
diseases like Type-1 Diabetes, Rheumatoid Arthritis, and Multiple Sclerosis.
Clinical Impact:
Restoring or enhancing Treg function is being explored as a promising
Disease Treg
Role
Type-1 Diabetes (T1D):
In T1D, there is a decrease in Treg number and activity, leading to
the failure of immune regulation. As a result, auto-reactive T cells
attack pancreatic β-cells, causing insulin deficiency and elevated
blood glucose levels.
Multiple Sclerosis (MS):
In MS, Tregs fail to suppress Th17 cells, which drive inflammation
in the central nervous system. This results in demyelination, where
the protective covering of neurons is damaged, impairing nerve
function.
Rheumatoid Arthritis (RA):
RA is associated with defective FoxP3 expression in Tregs. This
weakens their suppressive ability, leading to chronic joint
inflammation and tissue destruction.
Systemic Lupus Erythematosus (SLE):
In SLE, Tregs show reduced secretion of IL- 10, an anti-
Summary
Key Takeaways on Regulatory T Cells
(Tregs):
Maintain Immune Balance:
Tregs play a central role in controlling immune responses by
preventing
excessive activation of immune cells that could harm the body’s
own tissues.
Prevent Autoimmunity:
When Tregs are absent, reduced, or functionally impaired, the
immune system may mistakenly attack self-cells, leading to
autoimmune diseases such as Type- 1 Diabetes, Rheumatoid
Arthritis, and Lupus.
Regulate Inflammation:
By releasing inhibitory cytokines like I L - 10 and TGF-β, Tregs
suppress inflammatory pathways and maintain tissue
health.
Therapeutic Potential:
A deeper understanding of Treg biology can help in designing
targeted immunotherapies — either by boosting Treg activity in
autoimmune diseases or limiting it in cancers where they suppress
