Where do T cells come from?
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Where do T cells come from?. medulla. cortex. cortex. medulla. cortico-medullary junction. T cell development. Hematopoeitic Stem cell. Lymphoid progenitor. Lymphoblast. Prolymphocyte. Small lymphocyte. T lymphocyte. Lymphoblast. Lymphocyte. Development of the thymus.

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Where do T cells come from?

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Where do t cells come from

Where do T cells come from?

medulla

cortex

cortex

medulla

cortico-medullary junction


Where do t cells come from

T cell development

Hematopoeitic

Stem cell

Lymphoid progenitor

Lymphoblast

Prolymphocyte

Small lymphocyte

T lymphocyte

Lymphoblast

Lymphocyte


Where do t cells come from

Development of the thymus

The thymic epithelium develops as two flask-shape endodermal diverticula, arising from the third branchial pouch (pharyngeal pouch), and extending into the surrounding mesoderm and neural crest-derived mesenchyme in front of the ventral aorta. During the late stages of the development of the thymic epithelium, lymphoid cells from bone-marrow invade the thymus and aggregate to form lymphoid follicles.

The thymus grows between birth and puberty and then begins to atrophy (hormone related). Proportional to thymic size, thymic activity (T cell output) is most active before puberty. Upon atrophy, the size and activity are dramatically reduced, and the organ is replaced primarily with fat (involution).


Where do t cells come from

What happens if there is no thymus?

“Nude” mice are defective and lack a functional thymus. As a result, they have virtually no T cells. The impact of this on the acquired immune response is profound:

  • No cell-mediated immune responses requiring CD4+ and/or CD8+ T cells

  • No killing of virus-infected or malignant cells (no cytotoxic T cells)

  • Defective antibody formation (no CD4+ helper T cells)

  • No graft rejection (requires both CD4+ and CD8+ T cells)


Where do t cells come from

Double negative

Double positive

Single positive


Where do t cells come from

T-cell

development

POSITIVE SELECTION

Interaction with MHC

class I or MHC class II

on cortical epithelium

NEGATIVE SELECTION

Interaction with MHC class I or MHC class II + self peptide (dendritic cells, macrophages). AIRE protein expression (AutoImmune REgulator).


Where do t cells come from

T cells interact with antigen presenting cells through the T cell receptor (TCR) and MHC

T cell receptor

CD4

MHC classII

Helper T cell

MHC classI

Cytotoxic T cell

CD8

Antigen presenting cell


Where do t cells come from

T cell receptor genes rearrange in the thymus

Similar rearrangements occur at thea and d (the d locus is embedded in thealocus), b, and gloci. Thealocus is more diverse than theb(~100Vacompared to ~20 Vb). Theglocus is organised more similar to an antibodylight chain locus than the other TCR loci.

Vb (~20)

Jb1 (7)

Db1

Jb2 (6)

Vb1

Vb2

Vbn

D

J

D

J

J

J

J

J

J

Cb1

J

J

J

J

J

J

Vblocus (mouse)

rearranged DNA

D

J

Cb1

Vb1

spliced mRNA

transcript

J

Cb1

D

Vb1


Where do t cells come from

What happens next when T cells leave the thymus?

Lymphoid tissue homing receptors

CD62L+, CCR7+ T cells

B cell area

T cell area

blood vessel

Homing to mucosae and sites of infection

CD62L-, integrins a4b7+/a4b1+, CCR5+,

CCR3+ T cells

CD34

L-selectin

T

diapedesis

T

Naïve T cell

LFA-1

High endothelial

venule

ICAM-1


Where do t cells come from

T cell circulation through the lymph node

Dendritic cell interaction primes T cell

B cell area

T cell area

T cell

medullary chords

dendritic cell

T cell

afferent

lymphatic

blood vessel

High Endothelial

Venule (HEV)

efferent

lymphatic

germinal centres

T cells provide help for B cell expansion


Where do t cells come from

T cell activation… complexity prevents inappropriate activation

Dendritic cell

CD80/86

CD40

MHC II

CD28

TCR

T

CD40L

IL-4

T cell

B cell

ICOS

ICAM-1

(CD54)

LFA-1

(CD11a/CD18)

B7RP-1

LFA-3 (CD58)

CD2

CD40L

(CD154)

CD40

CD4

peptide

CD3

MHC II

T-cell

receptor

CD4

CD28

(CD80)

Only professional APCs express the gallimaufry of co-stimulatory molecules required to activate naïve T cells!

CD28

(CD86)

T cell

Dendritic cell


Where do t cells come from

There are several functional subsets of CD4+ T cells

Not all pathogens are the same, therefore the immune system has evolved ways of tailoring the immune response to suit the pathogen. Simplistically, Th1 cells promote a cellular response.

Type I pathogens (bacteria/viruses)

salmonella

HIV

NK cell

IL-12

mDC1

Antigen, IL-12 + IL-18

IFN-g

IFN-g

IL-18Ra

IL-12Rb2

Th1

LT-a

IL-12Rb1/b2

IL-12Rb1

IL-18R

IL-12R

T cell

  • Cellular Immunity

  • Tc cell proliferation

  • Increase macrophage activity

  • Help B cells produce antibody

IL-12


Where do t cells come from

There are several functional subsets of CD4+ T cells

Th2 cells produce cytokines that favour a humoral response and induce mast cell production.

Type 2 pathogens (helminths)

Ancylostoma caninum

IL-12Rb1

IL-12Rb1

mDC2

IL-4

IL-5

IL-13

IL-25

IL-12Rb2

Th2

IL-4

Antigen

IL-5

Basophil

Eosinophil

Mast cell

  • Humoral Immunity

  • B cell proliferation

  • Class switching e.g. IgA & IgE

  • Increase Ig production

IL-25

c-kit+

NKT

Immunity to parasites


Where do t cells come from

There are several functional subsets of CD4+ T cells

Th17 cells produce cytokines that promote neutrophil responses.

iDC

Treg

TGF-b

Antigen, IL-23 + IL-1/18

IL-6

mDC

IL-17A

IL-17F

IL-6

G-CSF

IL-23R

Th17

IL-12Rb1

IL-23R

IL-12Rb1

IL-18R

IL-23R

IL-23

Type 17 pathogens (bacteria, fungi)

G-CSF

Enhance neutrophil response

aspergillus

salmonella


Where do t cells come from

Cytotoxic T cells kill virus-infected cells

cytotoxic T cell

“cytotoxin”-containing granules

apoptosis

virus-infected cells

Perforin – aids delivery of granule contents into cytoplasm of target cell

Granzymes – Serine proteases, activate apoptosis by switching on Caspases

Granule contents

Granulysin – Activates apoptosis

IFN-γ – Inhbits viral replication, increases MHC I.

Macrophage activation

TNF-α, – Macrophage activation, apoptosis induction.

Cytokines


Where do t cells come from

…and finally… NK cells

NK cells recognise “stress” receptors on the surface of virus-infected and malignant cells. They can also detect reduced MHC expression.

NK cell

Infected cell

NK cells can kill infected cells by ADCC, they are rich in Fc receptor expression.

An inherited deficiency in NK cells has been described. Manifesting as recurrent EBV, CMV, VZV and HSV infections, NK cells must play an integral role in immunity to herpes viruses.


Where do t cells come from

Summary - Lymphocytes and their function(s)

Helper T cell

CD4

Provides help to other cells of the immune system to respond to infection

T cell receptor

Cytotoxic T cell

CD8

Kills cells infected with intracellular pathogens

NK cell

Innate immunity - cell killing and cytokine secretion


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