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The Nobel Prize in Physiology or
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Medicine for 2025 honors three
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researchers Mary Ibana, Fred Ramstell,
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and Shyman Saguchi for their
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revolutionary discoveries concerning
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peripheral immune tolerance. This video
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is a humble attempt to explain their
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groundbreaking discovery. First, let's
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begin with Shyman Saguchi's work, the
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discovery of regulatory tea cells or
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TRA. For understanding this we must know
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how T- helpper cells works and what do
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you mean by central tolerance in
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immunology. Let's begin with how T-
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cells works. So this is an infected
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cell. It engulfves the virus by
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and degrades it and a partic a fragment
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is presented on MSC receptor or HLA
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protein complex to the outside. So this
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is a particle of the virus that is
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displayed to the outside. So this is
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recognized by T- helpper cells or T-
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T- cells as you see there are different
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receptors for T cells or each T- cell
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with is with unique specificity that can
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bind to specific antigenic particles of
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the pathogen. So when a T- cell receptor
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attaches to this virus fragment, this T-
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cell is activated and alerts the immune
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system and triggers a coordinated
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specific immune response against it this
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pathogen by means of all other immune
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cells like B cells, macrofasages etc.
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and finally eliminating the pathogen
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from the system. So T- cells is actually
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regulating this specific immune
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response. Now the second concept that is
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central tolerance. Central tolerance is
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a process where T cells that recognize
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the body own proteins were eliminated
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while maturing in the thymus. Let me
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make it more clear. As we know the cells
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are also produced in bone marrow but
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maturation takes place in thymus.
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During this maturation
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each T- cell has an unique shaped T cell
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receptor on its surface. Then thyus cell
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holds out body zone proteins on a
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receptor to this T- cell. If the T- cell
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recognize body zone or self proteins
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that particular T- cell is destroyed or
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eliminated. This actually prevents
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overreaction or autoimmune response or
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response against self proteins or self
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cells. So this T- cell has to pass this
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test in order to become fully active. So
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T cells that pass this test go out into
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the body to look for intruders or
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pathogens. So this central tolerance is
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very crucial in avoiding overreaction or
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autoimmune response or identification of
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self- proteins or self cells by T cells.
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Now let us understand Sakaguchi's work.
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His hypothesis was that immune system
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must employ some form of security guard
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capable of calming down other T- cells
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that had slipped through the initial
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tolerance test in the thymus. Let us
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understand his hypothesis from his
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experiment. His experiment was he
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removed the thymus from 3-day old mice.
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So this mice developed autoimmune
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disease. As we know thymus is a site of
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maturation of tea cells. immune system
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will be overactive as this T- cells
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don't have that central tolerance or
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that test that eliminate T- cells that
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activate or that interact with self
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cells or self proteins. So immature T-
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cells attack self cells that's why this
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mouse becomes sick. Then he isolated
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mature T- cells from a genetically
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identical mice and injected that T-
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cells into this deceased mice and found
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out that the mice is healthy or this
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injected T- cells protected the mice
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from autoimmune reaction or autoimmune
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disease. These tea cells that is
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injected calm down or check the attack
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by immature T- cells that is already
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present in this mice that is capable of
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attacking self cells. So he concluded
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that there must be a protective cell
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type a security guard that keeps other T
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cells in check or T cells that escape
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this test of central tolerance. This is
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followed by a second experiment that
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discovered regulatory T cells. As we
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know T- helpper cells has CD4 plus
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protein on its surface. So this is a
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typical feature of T- helpper cells. He
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found out another class of T cells which
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is which has this CD4 plus protein.
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Along with that there is CD25 plus
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protein on its surface. Then he
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conducted the same experiment. A mice
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whose thymus is removed. He injected
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T cells only with CD4 plus only or T-
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helpper cells with only CD4 plus protein
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on its surface and found out that mice
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remained sick. Then he continued the
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experiment along with T cells with CD4
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plus protein. He added the cells with
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both receptors CD4 plus and CD25+
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protein on the surface and found out
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that then these cells actually protected
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the mice from developing autoimmune
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response. He identified a new class of
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T- cells. These cells help suppress or
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calm the immune response. they express
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both CD4 plus and CD25 surface proteins
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and he named them as regulatory T- cells
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identified a new class of T cells which
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is called as regulatory T- cells. Now
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the second part of the experiment
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carried out by Mary Mary Branow and Fred
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Ramstl discovery of Fox P3 gene. Mary
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Branow and Fred Ramstl became interested
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in a peculiar mouse train called scurfy
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mouse which originated in the US
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laboratory in the 1940s.
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These are the features of this mouse.
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This male scurfy mice showed fatal
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autoimmune like symptoms.
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Symptoms included scaly skin, enlarged
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organs and early death and there on tea
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cells attacked body tissues. So it's an
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autoimmune response. The mutation
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responsible was located on the X
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chromosome. So they wanted to find out
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the mutant gene that is responsible for
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this curfe condition and they firstly
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carried out the localization. They
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focused on X chromosome. It was known
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that this mutant gene is located on the
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So genetic mapping were conducted and
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narrowed down the location of the scurfy
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mutation to an area of 500,000 base
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pairs nucleotides and followed by detail
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mapping an intensive process of mapping
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this large area of DNA in detail. It is
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a herculan task with molecular tools
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available in 1990s. Then gene comparison
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after identifying 20 potential genes in
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that region. They systematically
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compared these genes between healthy
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mice and scurfy mice and finally they
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found out the mutation in the 20th and
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final gene they examined and they called
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it as fox P3 gene. The faulty gene was
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previously unknown but it had
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similarities to a group of genes called
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forut box or fox genes which regulate
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the activity of other genes. So they
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named this new gene as fox p3 gene. Then
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this was the second hypothesis. The
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human connection of this geneex disease
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in humans their hypothesis was it's a
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human variant of scurfy disease. So they
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suspected apex might be the human
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counterpart of scurfy disease. Working
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with pediatricians globally they
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collected samples from boys affected
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with Ipex disease and confirmed that
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harmful mutations existed in the human
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equivalent gene Fox P3. So mutations
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were found in the human fox P3 gene. In
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2001 they confirmed FOX P3 mutations
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cause both Apex and scurfy mouse
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disease. After this discovery, Saguchi
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and others convincingly proved that FOX
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P3 gene controls the development of
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regulatory T cells. So this gene is
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responsible for the development of
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deregulatory cells. So this was the
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experiment. So how this regulatory T
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cells protects us? Suppose a T- cell
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that has slipped through the test in
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thymus. So they can interact with
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proteone proteins that is presented on
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the cell surface. So endogenous protein
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that is presented on HLA receptor. So
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the these T cells can interact as it has
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slipped through the test. So this lead
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to autoimmune reaction then there will
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be an intervention by this petroleum
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regulatory T cells. These T- cells
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discover that the attack is a mistake
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and calm it down. thus preventing
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autoimmune disease. So this is the role
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of deregulatory cells calming down these
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cells that slip through dust in the
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thymus so that it can interact with self
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cells or self- proteins that interaction
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is calmed down by this deregulatory
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cells thus preventing autoimmune
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diseases. The collective discoveries of
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bronco ramstall and sakaguchi explained
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peripheral tolerance. So this is a
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summary. They explain the mechanism for
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peripheral immune tolerance. Regulatory
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T cells or T-Rex maintain peripheral
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immune tolerance. Their development is
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controlled by the FOXP3 gene. TRS act as
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a security guards preventing other T
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cells from attacking the body cells. The
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second role is it also helps in coming
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down the immune system after an invader
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or pathogen is eliminated from the
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system. So overreaction is avoided by
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means of deregulatory cells. So this is
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a summary of their work. Now let us see
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the clinical impact or significance. Why
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these findings fetch the Nobel Prize?
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First, it is widely used in the
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treatment of autoimmune disease.
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Researchers are attempting to promote
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the formation of more regulatory D cells
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using substances like interlucans 2 to
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stimulate deregulatory cell production.
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Another method is by isolating,
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expanding and returning T-Rex to
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patients to prevent autoimmune
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reactions. The goal is to prevent
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autoimmune reactions and also organ
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rejection post transplant. So research
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is going on in this aspect and is based
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on deregulatory cell. The second
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application is in cancer treatment.
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Tumors often attract large number of
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regulatory T cells which protect them
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from immune attacks as a shield.
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Scientists aim to break down this track
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wall so that other immune cells can
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reach and destroy the tumor. So research
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is going on in this aspect also. Their
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works explained peripheral immune
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tolerance that is mediated by
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deregulatory cells. Hope you are
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benefited from this video. Take care.
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Stay blessed. Thank you so much. You are
11:20
with biology exams for.com.
