Description

This video is about T-Lymphocyte Development and Function.

All information in my immunology videos is sourced from:

• Book: Immunology, Eighth Edition by David Male, Jonathan Brostoff, David Roth, and Ivan Roitt
• Additional research: PubMed
• University lecture materials

Development of T-Lymphocytes:

1. Origin: In red bone marrow as Multipotent Lymphoid Stem Cells.
2. Migration: Travel to the Thymus for further development.

Thymus:

• Grows to its maximum size around puberty, then gradually replaced by fat tissue.

Stages of T-cell Development in the Thymus:

1. Double Negative Stage: Ensure the cell lacks CD4/CD8.
2. Double Positive Stage: Ensure the cell expresses CD4/CD8.
3. Positive Selection: Ensure recognition of self MHC.
4. Negative Selection: Ensure no recognition of self-antigens.
5. Single Positive Selection: Cells become either:
   • CD4+ T-Helper Cells
   • CD8+ Cytotoxic T-Cells
6. Survivors travel to secondary lymphoid organs.
7. If a cell fails any stage, it undergoes apoptosis.

CD4+ Activation – T Helper Cells:

• Requires 3 activation signals to activate naïve T-cells:
  1. 1st Activation Signal: MHC – TCR (Receptor + CD4 + CD3).
  2. 2nd Activation Signal: B7 – CD28.
  3. 3rd Activation Signal: Cytokines:
     • IL-4: Induces differentiation into Th2.
     • IL-12: Induces differentiation into Th1.
• Activated T-helper cells secrete IL-2 (autocrine) for self-proliferation.

Functions of Activated T-Helper Cells:

Th2 Cells:

• IL-10: Suppresses Th1 response.
• IL-4, IL-5, IL-6: Stimulate B-cells for IgG, IgE, and IgA synthesis.

Th1 Cells (Inflammatory T-Helper Cells):

• IFN-γ (Interferon Gamma): Activates macrophages, promotes IgG synthesis, and inhibits Th2 response.
• IL-2: Helps the growth of B-cells and T-cells.

CD8+ Activation – Cytotoxic T-Cells:

• Virus-infected cells present antigen on:
  • MHC I: Non-professional APCs.
  • MHC II and MHC I: Professional APCs.
• Activation:
  1. T-Cytotoxic Cell binds to MHC I through TCR (3 activation signals required).
  2. Th0 binds to MHC II and differentiates into Th1, releasing:
     • IFN-γ and IL-2 to enhance cytotoxic T-cell activity.
• Mechanism of Killing:
  • T-cytotoxic cells undergo clonal expansion and express Fas-L to target Fas-expressing infected cells.
  • Release of:
    • Perforin: Creates holes in the infected cell membrane.
    • Granzyme B: Induces DNA fragmentation.

Th17 Cells:

• Important in fighting fungal infections.
• Severe fungal infections occur in immunosuppressed individuals.

Th17 Cell Development:

1. Macrophages phagocytose fungi.
2. Present three activation signals to naïve T-helper cells (Th0).
3. Macrophages release:
   • IL-1, IL-6, IL-23
   • Transforming Growth Factor Beta (TGF-β)

   → This differentiates Th0 into Th17.

Th17 Cell Functions:

• IL-17: Recruits neutrophils.
• Neutrophils: Promote inflammation via:
  • Granule release
  • Lysozymes
  • Reactive oxygen species
• IL-22 and IL-17: Stimulate epithelial cells to produce antimicrobial defensins.

T-Cell Tolerance:

• Eliminates cells that react to self-antigens.

Central Tolerance (In Thymus):

• Kills self-reactive T-cells before they mature.

Peripheral Tolerance (Outside Thymus):

• Self-reactive T-cells that escape to secondary lymphoid organs are inhibited through:
  • Clonal deletion (Direct inactivation).
  • T-Regulatory Cells (T-reg).

T-Regulatory Cell (T-Reg) Functions:

• IL-35: Suppresses immune function.
• IL-10: Decreases Th1 function.
• TGF-β: Inhibits macrophages.
• Regulates dendritic cells to prevent excessive immune response.
• Monitors IL-2 levels to regulate immune function.

How Many Days Does It Take to Gain Immunological Memory?

• Starts as a naïve cell.
• Clonal expansion: ~7 days.
• Effector response follows.
• Decreases until it becomes a memory cell.
• Memory cells persist and slowly decline after 14 days.

Transcript

Introduction
0:00
hello and welcome to another video in
0:01
this video I’m going to talk about the
0:03
t-lymphocytes development and functions
0:05
so let’s start with the development some
T-Cell Development
0:08
bones in your body has what we call
0:09
yellow bone marrow consisting mainly of
0:11
fat cells and we also have spongy bone
0:15
what we call red bone marrow which is
0:16
very very vascular lead and in the red
0:19
bone marrow most of our red blood cells
0:21
and lymphocytes are going to develop
0:23
including on T lymphocytes so let’s see
0:25
how they start the T cells in our body
0:27
start off as what we call multipotent
0:30
lymphoid stem cell then after that they
0:32
leave through the bloodstream to an
0:34
organ called the thymus now remember the
0:37
bone marrow and thymus are all called
0:39
primary lymphoid organs so the T in T
0:41
cell stands for the thymus which means
0:43
that it only starts off in the bone
0:45
marrow and then leaves and continue
0:47
their development at the thymus unlike
0:50
b-cells which develop in the bone marrow
0:52
that’s what the B stands for in the
0:53
b-cell so the thymus is very very much
0:57
like an University and I’ll take you
1:00
quickly through the education process of
1:02
how mature naive t-cells graduate
1:05
all right at first you know the thymus
1:07
the thymus will grow to its maximum
1:10
around here burley and then it will
1:12
gradually become replaced by fat and
1:14
connective tissue it does however still
1:16
have some sort of activity throughout
1:18
her life
1:19
so now let’s head into the university
1:21
and see what’s going on there are
1:24
initially five stages the cell has to go
1:26
through to graduate and you know the
1:28
thymus is not just a difficult
1:30
University it also twisted and scary
1:32
because all the cells that don’t pass
1:35
their exams will end up dead or and
1:37
thrown away in a process called
1:39
apoptosis so the first stage is what we
1:42
call double negative stage the goal here
1:44
is to check if the cells lack cd4 and
1:48
cd8 and that’s why it’s called double
1:50
negative stage because it literally
1:52
checks if you’re negative to both cd4
1:55
and cd8 here they do however Express CD
1:59
2 and CD 7 these are adhesion molecules
2:02
and also the T cell receptor starts to
2:04
develop here as well so if they do lack
2:08
cd4 and cd8 they can go to the next
2:10
stage which is what we call double
2:12
positive
2:13
stage which is basically checks if they
2:16
express cd4 and cd8 or not the TCR
2:20
receptor continues to grow at this stage
2:23
and also CD 3 is also formed the second
2:26
stage is the hardest exam it’s like a
2:29
histology exam or biochemistry exam over
2:32
95% of students fail here and end up
2:35
dead if they do express a divorce in a 7
2:38
though they can continue to stage 3
2:40
which is positive selection where you
2:43
basically check if cd8 I recognize
2:47
self-mhc 1 and if cd4 recognize self-mhc
2:50
2 and if those cells don’t really
2:53
recognize the self-mhc they go straight
2:55
to the garbage if it does however if it
2:58
positively binds to the MHC they
3:01
complete the stage and continue with
3:03
negative selection where they are
3:05
checked if they recognize self antigen
3:07
or not if they don’t recognize them if
3:10
they react to the self antigen the
3:13
teachers professor macrophage or doctor
3:15
that RIT Excel will eat them but if they
3:17
do recognize those self antigens and
3:19
don’t react they can then go to the last
3:22
stage which is the single positive
3:24
selection where they either become cd4
3:27
that graduate or a cd8 graduate and then
3:31
after that they can then migrate to the
3:33
secondary lymphoid organs to the spleen
3:35
or the other lymph node those are what
3:37
we refer to as the periphery so now
3:39
let’s see in details how the cd4 and cd8
3:42
function cd4 cells are what we refer to
How CD4+ (T Helper Cells) is Activated
3:45
as T helper cells and their main role is
3:48
to help other cells how I’ll show you
3:51
so imagine there’s an antigen presenting
3:54
cell right it phagocytes an antigen and
3:56
presented on MHC class 2 molecule and
3:59
then goes to the lymph node and present
4:02
it to a naive T helper cell also
4:04
referred to as T at 0 3 signals are
4:08
required to activate and differentiate
4:10
the cell the first signal is the T cell
4:13
receptor MHC complex where the T cell
4:16
receptor binds to the MHC with with a
4:19
peptide of course and cd4 kind of
4:22
strengthens the binding and
4:24
and that strong binding is going to
4:25
trigger cd3 into singing sending a
4:28
positive signal inside the cell so that
4:30
T cell receptor MHC complex is the first
4:34
signal first activation signal the
4:36
second signal being b7 with a cd28 now
4:40
to get at T helper cell to cell we need
4:43
interlocking 4 which comes from mast
4:46
cells or other T helper 2 cells or even
4:49
Vasa Fields can also release into the
4:51
King four to get T helper cell 1 however
4:54
the antigen presenting cell release
4:56
interlocking twelfth itself triggering
4:58
it to become a T helper cell 1
5:00
now these cytokines are the third signal
5:03
for for the 19th year per cell now for
5:06
this t-80 to keep growing and
5:09
differentiate it secretes out
5:11
interlocking 2 which binds to itself
5:13
receptor so this process of stimulating
5:16
itself is called autocrine now T helper
5:19
cell 2 secretes what we call
5:21
interlocking 10 which suppresses the th1
5:24
response now keep that among the th1 and
5:27
th2 are kind of enemies in that sense
5:30
that when you produce T helper cell 1 it
5:33
will switch off the T helper cell to
5:35
response and vice versa so interleukin
5:38
10 it also secretes out into looking for
5:41
interlocking five interlocking six all
5:44
of those stimulate the B cell into
5:46
secreting specific type of antibodies so
5:49
T helper cell 2
5:51
helps the B cell differentiate into an
5:54
antibody secreting plasma cell and a
5:57
memory cell and the way I remember that
5:58
is that you know T helper cell 2
6:01
it helps the B cell become 2 cells so TS
6:05
to help the B cell become 2 cells plasma
6:08
cells and B cells that’s how I remember
6:10
that the THC will help the B cell
6:12
differentiate so it becomes that after
6:15
receiving into looking for th one
6:17
however it’s what we call inflammatory T
6:19
helper cell because it mainly triggers
6:22
the macrophage into releasing
6:24
inflammatory cytokines so interferon
6:27
gamma activates a macrophage and also
6:29
stimulates B cells into secreting a
6:32
cific subtype of IgG and also here we go
6:36
th one switches off the function of T is
6:38
to it also secretes out interlocking to
6:41
which helps B and T cells to grow as you
6:44
see here so T helper cell one from
6:47
interleukin 12 cd8 however is called
How CD8+ (T Cytotoxic Cells) is Activated
6:50
cytotoxic T cell imagine the virus right
6:54
it can infect both normal cells or
6:57
antigen presenting cells and if it
6:59
infects normal cells now I’ll talk more
7:02
about this later when I talk about the
7:04
cellular immune response but normal
7:06
cells become non professional antigen
7:08
presenting cells because they can
7:11
express a part of the virus on MHC class
7:14
1 because all nucleated cells has MHC
7:16
class 1 molecule but doesn’t really
7:18
express b7 and b7 remember is a very
7:22
important co-receptor to activate T
7:24
cells it doesn’t have that that’s why we
7:25
called a non-professional antigen
7:27
presenting cell
7:28
it’s normally phagocytosed by the
7:30
antigen presenting cell either way the
7:33
professional antigen presenting cell
7:35
will express the peptides of the virus
7:38
on both MHC 1 and MHC 2
7:40
this mechanism is called a cross
7:43
presentation right and and and the
7:45
dendritic cells are very good at cross
7:47
presentation because they’re very big
7:50
and they have processes and they can
7:51
activate different kind of cells at the
7:53
same time so co-stimulation is a very
7:55
specific function for the dendritic cell
7:58
now on MHC class 1 a naive t-cells toxic
8:02
cells can bind
8:03
remember 3 activation signals are
8:05
required to activate the T cells the
8:07
first one is with a t cell receptor on
8:10
the MHC or we got the cd8 that binds cd3
8:14
is activated this is a T cell receptor
8:17
MHC complex that’s the first signal the
8:19
second signal is with b7 and cd28 and
8:23
now before we continue at the same time
8:27
it also helps at T at zero differentiate
8:30
to th one by secreting interlocking 12
8:33
or it can also differentiate into a th
8:36
one by interference from natural killer
8:39
cell for example and now with
8:40
interlocking – a differentiation and and
8:43
clonal expansion
8:44
and this active th1 will then give the
8:47
third signal to the T cell toxic cell to
8:50
further differentiate which is the
8:51
interferon gamma and interlocking to
8:53
right and after it receives them it will
8:56
undergo clonal expansion and start to
8:59
express a receptor called fast ligand or
9:01
FAL now what does it do
9:04
you know any type of infected cell will
9:07
express FAS as well as presenting the
9:10
peptide on a surface it’s like it’s like
9:13
an alarm saying hey I’m infected please
9:15
come and kill me so as they bind the T
9:19
syntactic cell will release preference
9:21
which makes holes on the surface of the
9:23
cell and brands on B which kind of
9:26
fragments their DNA to kill the cell at
9:31
the same time the active T helper cell
9:34
one expresses cd4 T L say for a ligand
9:37
which triggers the macrophage together
9:41
with interferon gamma to kill the
9:44
remaining viruses so that’s mainly had a
9:47
cd4 and cd8 function and there’s
9:49
actually going to be a lot of other T
9:51
helper cells as well not to see helped
9:53
us a lot in T helper cell to you I’m
9:55
only going to mention T helper cells 17
9:58
and T cell tolerance in this video all
Th17 (Activation/Function)
10:01
right
10:01
so T helper 17 is gonna be really good
10:04
against infections by fungi so let’s say
10:07
this blue dot says it’s gonna represent
10:09
the fungi right severe fungal infection
10:12
can be seen in patients with untreated
10:15
AIDS for example or patients with cancer
10:18
and undergo chemotherapy so during a
10:22
fungal infection you’ll normally
10:23
normally be recognized by antigen
10:26
presenting cells via for example Tolec
10:29
receptors or mannose receptors for
10:32
example then it’s gonna phagocytose it
10:35
and then presented on MHC class 2
10:39
molecule as you see here and what binds
10:42
best to MHC type 2 molecule that’s gonna
10:44
be naive T helper cell so the first
10:47
activation si not remember that’s going
10:49
to be T cell receptor and MHC class 2
10:51
with the cd4 is gonna work as an anchor
10:53
and then that’s gonna activate the c-d-c
10:56
three years after into
10:57
sending a positive signal to the cell
10:58
nucleus that’s the first activation
11:00
signal the second activation signal
11:02
remember is b7 together with cd28 and
11:05
the third activation signal now we need
11:10
th17 and to get that we need don’t get
11:15
scared about all of this we need
11:17
interlocking 1 or interlocking 6 or
11:20
interlocking 23 or transforming growth
11:24
factor beta after receiving all of these
11:28
the interlocking 1 623 and tgf-beta the
11:31
naive T helper cell remember is gonna do
11:33
that outer green function with the
11:35
interlocking 2 to start growing and then
11:37
it can start to differentiate and divide
11:40
into active th17 cells and why are they
11:44
called T T helper cells 17 because
11:46
they’re specialized into the releasing
11:48
interleukin 17 and they can also release
11:51
intellect in 22 intelligence 17 is going
11:55
to recruit neutrophils and neutrophils
11:58
is going to promote inflammation
12:01
you know neutrophils can secrete
12:03
granules which can kill microorganisms
12:05
and same as fungi and at the same time
12:09
by releasing reactive oxygen species and
12:12
maybe also some lysozymes can can also
12:15
damage tissues and activate them and
12:17
promote inflammation but intellect in 17
12:20
interlocking 22 they both have a common
12:23
function which is that they can
12:25
stimulate epithelial cells to produce
12:27
antimicrobial proteins like different
12:30
things for example defin sins have a an
12:33
anti fungal and also antimicrobial
12:35
property by a binding aggregate in
12:39
optimizing the fungi to promote
12:42
phagocytosis so different things are
12:44
very very important in anti fungal
12:46
immunity now another thing that’s very
12:49
important when it comes to anti fungal
12:51
immunity is that we don’t only get T
12:54
helper cell 17
12:55
we also get T helper cell 1 and remember
13:00
interlocking 12 in the dendritic cell
13:02
can release interlocking 12 instead of
13:04
T’s interacting 23 in token 6 and 13 1 +
13:08
T TS better
13:10
but they can also release interlocking
13:12
12 which can direct the naive T helper
13:15
cell into becoming a th one cell and
13:17
what did he t helper cell one do
13:19
remember that they are very good at
13:22
activating macrophage they are also
13:25
called inflammatory T helper cells and
13:28
how do they do that remember they have
13:29
cd40 ligand which bind to say the 40 on
13:32
the macrophage with the help of
13:34
interferon gamma is going to activate
13:36
this macrophage into releasing
13:39
inflammatory cytokines or
13:41
pro-inflammatory cytokines which are
13:42
interlocking one interlocking six and
13:44
tumor electrode factor alpha so when you
13:47
think of fungi think of everything
13:49
that’s gonna promote inflammation and
13:51
remember what these did they are also
13:54
stimulate the epithelial cells they
13:56
cause vasodilation they can also go to
13:59
they have a systemic response they can
14:01
go to hypothalamus and release
14:03
particular dingy – and that will cause
14:05
fever and also intelligence IgG single
14:08
deliver and also stimulated to release
14:11
acute phase proteins like CRP or mannose
14:14
binding lectin protein so all of this
14:17
happened because we have an infection
14:20
against fungi so you see now how
14:22
important that T helper cell 17 is just
14:24
remember these cytokines right here that
14:28
they are related to T helper cells 17
14:31
the interlocking one interleukin 6 in
14:33
1323 and transforming growth factor beta
14:36
and that T helper cell 17 can release
14:40
interleukin 17 and interlocking 22 cool
14:44
now lastly I want to talk about T cell
T-Cell Tolerance (T-Regulatory Cells)
14:48
tolerance T so tolerance is basically
14:51
eliminating cells that react to self
14:54
antigen so we mainly have two types of
14:57
teeth of Tolerance we have something
14:59
called central tolerance in the thymus
15:02
and we just looked at this the at the
15:04
development remember the stage stage
15:06
four with the negative selection where
15:08
immature
15:10
t helper cells is presented to a self
15:13
antigen and if it doesn’t recognize it
15:15
if it reacts to the self antigen is
15:17
going to be killed but you know our body
15:21
isn’t perfect some some mistakes can
15:23
have
15:23
and they can escape to the periphery and
15:26
there we have peripheral tolerance the
15:28
extra times there either direct
15:31
inactivation happen or t-regulatory self
15:34
happen about 10 to 15 percent of the T
15:38
cells in the lymph nodes consist of T
15:40
regular cell and they cannot they
15:42
regulate the inflammation so that we
15:45
don’t have too much nor too little and
15:48
these cells are characterized by
15:50
expressing Fox p3 cd4 and cd8 25 C of 25
15:55
s gonna be interacting two receptor now
15:57
I’m not going to go into more detail to
15:59
this I’m just gonna show you how a T
16:01
regulatory cell function so imagine a
16:05
dendritic cell T cell and a regular cell
16:08
right the T regulatory cell is very good
16:11
at secreting interlocking 35 interleukin
16:14
10 and transforming growth factor beta
16:16
interlocking 35 suppresses the immune
16:19
function interlocking 10 kind of
16:21
decreases the the function of T helper
16:24
cell 1 which is indirectly involved with
16:27
macrophages because they are
16:28
inflammatory cells remember that’s how
16:30
it regulates the DD inflammation and a
16:33
transforming growth factor beta also
16:35
inhibits the macrophage and with the
16:38
help of these cytokines they can
16:39
actually deactivate the functions of the
16:41
dendritic cell but what can also do is
16:44
that you know it expresses cd25 which is
16:47
interlocked interior receptor you know
16:50
when a t-cell is activated with antigen
16:52
it’s gonna release a lot of intellection
16:55
to right to either activate itself or to
16:57
activate others T regulatory cells can
17:00
actually sense that there’s a lot of
17:02
interaction to release and say hey easy
17:04
now there’s already too many cells
17:06
active and then it could downgrade it so
17:09
that so to keep a balance now lastly how
Time Needed for Immunological Memory
17:14
many days does it take to gain
17:15
immunological memory on day zero they’re
17:19
naive right and then when they get
17:21
stimulated they go into clonal expansion
17:23
and their number is going to increase
17:26
until it reaches a peak of affective
17:29
response and then after that is going to
17:32
go slowly decrease as memory cells start
17:35
to show
17:36
and this Cana is stabilized at 14 days
17:39
and then goes down very slowly after
17:41
that so it usually takes 14 days to gain
17:44
memory so that was mainly everything I
17:47
wanted to talk about and I hope this was
17:49
helpful