Immunology Lecture 08
T Cell Development and
Thymic Education
Dr. Rabiul Haque
Lecturer, Department of Pathology
Holy Family Red Crescent Medical College, Dhaka
· Subscribe to
youtube.com/c/RabiulHaque for more
pathology video lectures.
· Visit pathologytutorials.weebly.com for
transcript of uploaded lectures.
· Visit facebook.com/Pathology.Tutorials
for channel updates.
Learning Objectives :
Introduction
Definition
Overview of T Cell Development
Thymus
αβ T Cell Development
γδ T Cell Development
NK T Cell Development
Introduction
The development and differentiation of lymphocytes are
regulated by adaptive immune system carefully.
Self reactive T and B cells are removed before they
become fully functional.
Definition
The process by which lymphocyte progenitors in the
thymus and bone marrow differentiate into mature
lymphocytes that populate peripheral lymphoid tissues is
called lymphocyte development or lymphocyte maturation.
Ref. Cellular and Molecular Immunology, 9th Edition
Overview of Lymphocyte Development
Hemopoietic stem cells in the bone marrow give rise to
Common Lymphoid Precursor (CLP) of lymphocytic lineage
cells.
They either differentiate within the thymus to give rise to T
cell lineage of cells or remain in the bone marrow to give rise
to B cell lineage of cells.
Development of T cells involves sequential rearrangement
and expression of “TCR genes”, cell proliferation, antigen-
induced selection processes and commitment to subsets
that are distinct both phenotypically and functionally.
Multipotent Stem Cell
Myeloid Stem Cell Lymphoid Stem Cell
B Cell T Cell NK Cell
Plasma Cell T-helper Cell T-cytotoxic Cell
Overview of Lymphocyte Development
T lineage cells differentiate along one of three
developmental pathways within the thymus.
- Those that express αβ TCRs
- Those that express γδ TCRs
- Those that share functional properties of NK cells
Thymus
• It is a lobulated primary lymphoid organ.
• It has very important role in cell mediated
immunity.
• Embryologically thymic epithelium is derived from
3rd and inconstantly 4th pair of pharyngeal
pouches.
• Thymic lymphocytes are mesodermal in origin.
Thymus
It weighs 10 to 35 gm at the time of birth.
Then grows until puberty to gain maximum weight
of 20 to 50 gm.
After puberty it progressively involutes.
In older adults it weighs little more than 5 to 15
gm.
Thymus
It is bilobed and encapsulated.
Fibrous extensions called trabeculae extend inward
from the capsule and divide each lobe into multiple
incomplete lobules.
Each lobule has outer cortical layer and central
medulla.
Since the lobules are incomplete medulla shows
continuity between the neighboring lobules.
Thymus
It is populated by diverse types of cells.
Prothymocytes are T cell precursors, they
migrate from bone marrow to the thymus attracted
by thymic molecules (e.g. lymphotactin).
Upon entering the thymus at corticomedullary
junction they are named thymocytes.
Thymus
The thymocytes will then undergo strict positive and
negative selection process as they migrate from
thymic cortex to medulla driven by chemokines.
Only 1 to 5 % of all thymocytes pass the selection
tests to graduate as T cells.
The other 95 to 99 % either die by apoptosis after
failing one of the selection tests or leave the thymus
before undergoing selection.
Thymus
Other cells in the thymus are called epithelial
reticular cells that include dendritic cells,
macrophages and epithelial cells.
Dendritic cells derived from bone marrow and
they are present at corticomedullary junction and
within the medulla.
Macrophages are primarily present in the
medulla.
Thymus
The epithelial reticular cells serve as instructors
for the thymocytes.
Hassall's Corpuscles:
- Oval structures consisting of round or spherical
aggregation of flattened epithelial cells.
- Composed of central mass and a capsule
formed of epithelioid cells.
αβ T Cell Development
Newly derived cortical thymocytes are Double
Negative (DN) cells (CD4- , CD8- ,TCR- , CD3-).
Soon they generate and express CD4, CD8, CD3
and recombine their TCR genes to generate unique
TCRs.
Since they express both CD4 and CD8 on their
surface they are called Double Positive (DP) cells.
αβ T Cell Development
DP thymocytes will undergo a strict positive
selection test and those failing the test will die by
apoptosis.
Positive Selection is the process in which
thymocytes whose TCRs bind with low avidity to
self peptide-self MHC complex are stimulated to
survive and to differentiate either into CD4+ or CD8+
T cells.
αβ T Cell Development
DP cells failing this step can make further attempts as
all cells have maternal and paternal alleles of their
TCR genes.
DP cells stuck at this stage can continue to mutate
and re-audition TCR genes to make more suitable
TCRs.
DP cells failing to recognize and bind to self MHC or
pMHC (peptide+MHC) molecules expressed by
cortical APCs will die by apoptosis within 3-4 days.
This type of death is also called death by neglect.
αβ T Cell Development
During transition from DP cells to Single Positive (SP)
cells, thymocytes whose TCRs recognize self class I
MHC molecules become CD8+ CD4-.
Similarly thymocytes whose TCRs recognize self class
II MHC molecules become CD4+ CD8-.
This is sometimes referred as rule of eight.
Cells passing the positive selection test and located at
the corticomedullary junction are allowed to enter the
medulla.
αβ T Cell Development
What is the importance of positive selection?
It guarantees that T cells that eventually exit the
thymus have functional TCRs that can bind to self
MHC molecules.
αβ T Cell Development
Survivors of positive selection will undergo a second
selection test called negative selection when they
arrive at the corticomedullary junction.
Here they interact with second set of epithelial reticular
cells expressing self antigens.
αβ T Cell Development
In the medulla, thymic epithelial cells express a nuclear
protein called AIRE (autoimmune regulator).
AIRE induces low-level expression of many antigens
that are normally expressed only in specific peripheral
organs.
Tissue-restricted self-antigens can be expressed in the
thymus due to action of Autoimmune regulator (AIRE).
Thymocytes whose receptors recognize peptide–MHC
complexes with high avidity undergo apoptosis (called
negative selection) or differentiate into regulatory T
cells.
αβ T Cell Development
What is the importance of Negative Selection?
It ensures that naive T cells that will exit the thymus
are not specific for self antigen.
αβ T Cell Development
Thymocytes that pass both positive and negative
selection tests have graduated from the thymus.
They enter the circulation through the medullary
post capillary venules as T cells.
Bone Marrow Thymus Lymph Node
CD8+ Cytotoxic Th1
T Cell T Cell
T Cell CD4+CD8+
Precursor T Cell
Th2
CD4+ Helper
T Cell T Cell
Th17
Treg
Bone Marrow Thymus Lymph Node
CD8 CD4
TCR
CD8+ Cytotoxic Th1
T Cell T Cell
T Cell CD4+CD8+
Precursor T Cell
Th2
CD4+ Helper
T Cell T Cell
Th17
Treg
Bone Marrow Thymus Lymph Node
CD8+ Cytotoxic Th1
γ
T Cell T Cell
I F N-
- 12, -10
T Cell CD4+CD8+ L IL
Precursor T Cell + I -4,
- IL
IL-4
+ I L-2, Th2
N-γ
- IF
CD4+ Helper
T Cell T Cell +T
GF-
β, I
L-6
+
TG
F-
β
Th17
Treg
γδ T Cell Development
In fetal thymus, first TCR gene rearrangement
involves the γ and δ loci.
In developing double negative T cell, initially
rearrangement of TCR β, γ and δ is possible.
If a cell succeeds in productively rearranging its TCR γ
as well as its TCR δ loci before making a productive
TCR β rearrangement, it is selected into the γδ T cell
lineage.
This occurs in about 10% of developing double-
negative T cells.
γδ T Cell Development
Many of these cells fail express CD4 and/or CD8.
So they do not undergo positive and negative
selection tests like αβ T cells.
They depart from the thymus shortly after
developing their TCR complexes.
These T cells are thought to be transitional cell
types that may be a bridge between innate and
adaptive immune system.
γδ T Cell Development
In 90% of the time, a productive TCR β gene
rearrangement is made first.
Pre-TCR signaling selects these cells to mature into
the αβ T cell lineage.
NK T Cell Development
NK T Cell Development
Share some characteristics with NK cells.
Express several surface markers and receptors
found on NK cells.
Undergo some development in the thymus and
express TCRs.
Specifically recognize epitopes presented by a
"non-classical" MHC class I molecule called CD1d
.
50,000
Subscribers!
Thank You!
youtube.com/c/RabiulHaque
