T cells Development

By
Selda S. Ezzel-deen
Objectives:
1- T cell development
2- MirRNA role in T cells development.
3- T cells types and their Markers.
4- T cells function and life span.
5- T cells receptors.
7- T cells activation.
8- Microorganisms that effect T cells.
9- Some important T cell disorder.
 Major Cell Subtypes Functions
Types
Regulates response to
TH1
intracellular pathogens

Regulates response to extracellular

T helper TH2 pathogens
(TH)
Regulate cell-mediated
TH17 immunity
Regulate humoral immunity and
TFH B-cell development
T cells
TREG Inhibits immune response

T cytotoxic Eliminate cells displaying foreign

(TC)(CTL) antigen
Why T cell development is critical (important)?
Classify T-cell development into two phases:
 Early thymocyte development, during which diverse
TCR population of immature T cells is generated.
 And selection events that depend on TCR interactions
to shape this population so that only those cells that
are self-restricted and self-tolerant will leave the
thymus to populate the periphery.
Development of T cells from
hematopoietic stem cells on
bone marrow stromal cells
expressing the Notch ligand.
Early thymocyte development
 There, they go through a variety of different
stages
 Double negative (DN)—no CD4 or CD8
 Double positive (DP)—both CD4 *and* CD8

 Positive/negative selection stages to become

single positive—only CD4 *or* CD8
 Final screening to remove autoreactive cells
 Release into the peripheral bloodstream
Early thymocyte development
Early thymocyte development
Early thymocyte development
Early thymocyte development
TCR formation
TCRs formation
 TCRs formation

 Thymocytes can express either TCRαβ or

TCRγδ receptors
 TCRβ rearrangements are one of the first to take
place, and one of the most likely to be productive
 TCRs formation

However, TCRγδ are more common in fetal development

Reasons aren’t clear; fetal developmental environment
may provide different signaling cues
TCRs formation
 TCRs formation

* CD44, an adhesion molecule; and CD25, the a chain of the interleukin (IL)-2 receptor
Cells in transition from the DN2 to DN3 stages continue to
rearrange their TCR γ, TCR δ, and TCR β chains and make
the first major decision in T-cell development:
Whether to join the
• TCR-γδ or
• TCR-αβ T-cell lineage.
Those DN3 T cells that successfully rearrange their β chain
typically commit to the TCR-αβ T-cell lineage.
 TCRs formation β-selection

• DN thymocytes undergo β-selection, resulting in

proliferation/differentiation
• A successfully produced β chain is paired with the pre-
Tα chain
• Allows for formation of a pre-TCR complex (with CD3
proteins) and numerous early signaling events
Immature T cells
 The successful assemble of
TCR ends the early T
cells development
 Immature T cells are now CD4 and
CD8 double positive
Also has to have a CD3 complex
associated with it.
• After β-selection has occurred, thymocytes are at the DP stage
of development
• Functional TCRα chain replaces surrogate (non- functional)
pre-TCRα
• The cell still expresses both CD4 and CD8 (DP)
• Pos./neg. selection occurs, yielding mature single positive SP T cell
Immature signaling pathways DP Mature signaling pathways SP
 CD3

CD4
CD8
Positive and negative selection
Positive and negative selection

 DP thymocytes make up 80% of thymic cells

 These cells undergo thymic selection
Positive selection
Selects thymocytes bearing receptors capable of
binding self-MHC molecules, resulting in MHC
restriction

 Most cells (95%) fail positive selection and fail to

receive needed survival signals
 Positive selection
 T cells undergo positive selection
 Thymic epithelial cells express high levels of MHC class I and II
 Developing T cells can “browse” possible self-peptide/MHC
complexes
 Positive and negative selection

 These present self-peptides; three possible outcomes

when T cells encounter these self-peptide/MHCs
 TCRs can’t bind; cells die by neglect
 TCRs bind too strongly; negative selection (deletion)
occurs
 TCRs bind “just right”; positive selection to single-positive
stage occurs
 Positive and negative selection
 Positive selection ensures MHC restriction
 Most cells die by neglect before they could reach a
negative selection stage
 No binding to MHC complexes
 Those that can bind MHCs shift from DP to SP
 If the TCR can bind to an MHC class II molecule, it also binds

with the CD4 molecule, selecting the cell to the CD4+ subset
 The opposite happens if the TCR binds to an MHC class I
molecule, resulting in selection to the CD8+ subset
 TCRs can’t bind;
cells die by
neglect
 The thymus had a capacity to express and present
proteins from all over the body.
 This capacity was a unique feature of medullary thymic
epithelial cells (mTECs).
 mTECs express a unique protein, AIRE, that allows
mTECs to express, process, and present proteins that are
ordinarily found only in specific organs. (Epigenetic)
 Not all tissue types are in the thymus
 How does screening against these tissue antigens
take place?
 Autoimmune regulator (AIRE) protein induces
expression of many tissue-specific proteins in thymic
epithelial cells
 New T cells can be screened against these antigens
safely in the thymus
 Cytokines Function
Legends Naïve T cells are

CD3
Il-12 also known as
NIAVE T
resting T cells that
CD4 Cell IL-4 circulate in the
CD45
blood, waiting to
TCR α/β
TGFβ
be activated by

IL-6 antigen presenting

IL-2
 Function
Legends Cytokines Macrophage
CD3
IL-2
CD4
activation
IFN-γ
LT-βR
Th1 leading to
CD 366 TNF-α
increased killing
LT α
of intracellular
.pathogens
 Legends Cytokines Function
CD3
IL-4 Regulates
CD4
CD119 (IFN-γ Rα)
IL-5 response to
IL-6
CD193 (CCR3)
Th 2 extracellular
IL-33Rα
IL-10 pathogens
Legends Cytokines Function
CD3
IL-17A Regulate cell-
CD4
IL-17F mediated
TCR α/β Th 17
CD161 IL-22 immunity
IL-23R
 Cytokines
Legends Function
CD3
IL-10 Inhibits
CD4 Threg TGF-β immune
CD25 (IL-2Rα)
response
IL-35
CD39
LAP (TGF-β)
 Cytokines Function
Legends Regulate
CD3 IL-6 humoral
CD4 Thflh IL-10 immunity and
TCR α/β B-cell
IL-21 development
CD154
Legends Cytokines Function
CD3
Immune
IL-9 response against
CD4 Th9 IL-10 extracellular
TCR α/β
.parasites
Legends Cytokines Function
+CD3 Eliminate cells
TNF-α
T displaying foreign
antigen
+TCRαβ
CD8
-CD4

+CD8α

+CD8β
T cells Life span
• NIAVE T Cell

5-7 weeks
• The Effector T cells:
Have a limited life span and are eliminated at the end of the response.
• Memory cells:
Typical memory cells, by contrast, tend to be long-lived and may
survive for the lifetime of the animal (up to 50 years).
Thanks