TCR and T lymphocyte

development in thymus

Students should know:

Structure of TCRs
CDRs
Differences of recognized antigen between TCR and immunoglobulins (Ig)
TCR germ line configuration and rearrangements
TCR specificity
Clonality of T cells
Differences between TCR and chains

T cell receptor gene rearrangement and lineage commitment

preTCR
Positive selection
Negative selection
Changes in CD4/CD8 expression during T cell maturation in thymus.
The order and location of T cell selection
Cell types involved in T cell selection
Why is it important to match MHC molecules between donors and recipients for bone marrow
transplantation (for donor-derived T cells to be functional in recipients)?

Ifyoudontnotmakeantigenreceptors(asinSCIDpatients),

Figure 3-4

OralThrush

youcannotmakeTandBcellsandaresusceptibleevento
opportunisticpathogens(e.g.C.albicans)

CORE

9.
a.

Tlymphocytes
Tcellorigin(bonemarrow)andeventsassociatedwithmaturationinthethymus
(cytokines:IL1,2,3,6,7,GMCSF;thymichormones)
(1)Stemcells(multipotent)migratetothymusandmovefromcortextomedulla
whileinteractingwithMHCClassIIbearingnurse,epithelialandinterdigitating
cells.
(2)Maturationprogression:
(a)Earlythymocyte(CD48,Tcellreceptor(TCR)generearrangements)
(b)Commonthymocyte(CD4+8+,Tcellreceptorgenerearrangements;lowTCR
andCD3surfaceexpression)
(c)Maturethymocyte(CD4+orCD8+subsets;highTCRandCD3surface
expression;somaticrecombinationofTCRgenes)
(d)PositiveandnegativeselectionoccursandmostselfreactiveTcellseliminated.
(e)AllTcellspositiveforTCR,CD2,3,and28

CORE

b.

T cell antigen receptor (genetics, structure, accessory

proteins and signal transduction)
(1)
Antigen-specific TCR dimers: (90-95% of all T
cells) or ;
V, D, J, and C (constant) genes for and chains;
V, J, and C genes for and chains.
(2)
CD3 complex associated with TCR has a
signal transduction role.

Similarity between TCR and Ig

Both:
Bind antigen
Have variable region
Constant region
Each binding site is a
heterodimer (composed
of 2 different chains)
TCRs act only as receptors
Igs act as receptors and
effector molecules
(soluble antigen-binding
molecules)

TCRcomplex

Figure 3-6

CD3chainstransmitsignals

Figure 3-7

Origin, generation and differentiation of T cells

T cell progenitors migrate from bone marrow and seed thymus. T cell progenitors undergo
differentiation to CD4, CD8 and NKT cells in thymus. Mature CD4 and CD8 T cells
circulate between blood and lymphoid tissues until they meet antigens presented on
dendritic cells in lymphoid tissues. T cells further undergo maturation to become
functional memory or effector T cells in LT

Figure 5-2 Thymic involution: Human

thymus is fully developed
before birth and increases in
size until puberty. It then
progressively shrinks during
adult life.
Most thymectized adults have
no problem in T cell
immunity because they have
enough memory T cells in the
periphery, and these T cells
are long-lived.

Differentiation

Figure 5-3 part 1 of 2

DN(CD4CD8)and
DP(CD4+CD8+)
Immature
thymocytesarehere

MorematureSP(CD4+CD8
orCD8+CD4)thymocytes
arehere

Figure 5-3 part 2 of 2

TCR genes undergo DNA rearrangement in thymus

*No Ds in Vgene; DJ first then VDJ in gene rearrangement

Un-rearranged
rearranged
expression
rearranged
Un-rearranged

TCRgenerearrangementgenerates
theTCRrepertoire

Pre-TCR complex stops

further gene rearrangement at
locus, and induces
thymocyte proliferation

Finally TCR+ DP cells are

made

Two chances for productive (=correct

reading frame) rearrangement: chain

Successful rearrangement at one copy blocks that at the other

chromosome.

Multiple chances for productive (=correct

reading frame) rearrangement in chain

Successful rearrangement at one copy does not block that at the other.
Therefore, many T cells express two different chains.

Lineage commitment to or T cells

Successful gene rearrangement in

and before T

Successful gene rearrangement in

before or pT T (not
committed yet). This signals to
halt rearrangement of the and
-chain genes and to enter a phase
of proliferation.

Further rearrangement in and

. Lineage commitment now
depends on whether a functional
or T-cell receptor is made
first.
More T cells are made than
T cells

MostTcellsdonotexpressCD4orCD8.

Figure 3-8 part 2 of 2

Theyarethoughttobe:
Firstlineofdefense?
Bridgebetweeninnateandadaptiveresponses?

 T cells recognize a limited set of unusual antigens:

Figure 3-8 part 2 of 2

Small microbial compound (E)-4-hydroxy-3-methyl-but-2-enyl

pyrophosphate (HMB-PP, an essential metabolite in most
pathogenic bacteria including Mycobacterium tuberculosis and
malaria parasites, but is absent from the human host).
Host MHC class 1b: T10/22, MICA, MICB (structure similar to
MHC I; expressed by transformed or stressed host cells)
Nonprotein alkylamines (derived from microbes and plants)
Bacterial products: Mycobacterial HSP (heat shock protein),
superantigens (SEA)
Host heat shock proteins
Do not need antigen processing and presentation on MHC
molecules.

CD8 binds MHC class I

CD4 binds MHC class II

Most mature T cells are either CD4+ or CD8+.

CD8 T cells kill cells infected with intracellular pathogens or tumor cells
while CD4 T cells regulate (activate or suppress) other immune cells function (e.g.B cells and
mac).

ThestructuresofCD4andCD8

Figure 3-10

CD4+CD8+ DP cells: To be CD4 or CD8?

Interaction of DP cells with Ag:MHC I CD8+ T cells

Interaction of DP cells with Ag:MHC II CD4+ T cells
Thus, the antigen-specificity of TCRs determines the fate.

To survive in thymus, T cells need to bind self MHC (but not

too strongly).

Positive selection
(DP stage)

Negative selection
(SP stage)

Self MHCs shape the TCR repertoire. Individuals with different MHCs will
have different TCR repertoire. Most DP thymocytes dont survive to become
SP cells.

Positive selection selects T cells that recognize peptides

on self MHC
This is to assure that mature T cells can respond to antigen-presented on self
MHC.
-Self MHC I and II harboring self peptides on thymic epithelial cells recognize
and activate TCRs on some DP thymocytes.
-DP thymocytes should receive this signal within 3-4 days to survive.
Otherwise they undergo apoptosis.

NegativeselectioneliminatesTcellswithTCRsthat
bindtoostronglytoselfantigen/MHCcomplex.
ThisistoassurethatTcellsdontreactagainstselfantigens.Inother
words,autoreactivecellsareremovedbythisprocess.
Dendriticcellsandmacrophagesincorticomedullaryjunction
mediateit.
NegativeselectioncannoteliminateTcellswhosereceptorsarespecific
forselfpeptidesthatareexpressedoutsideofthymus(Thesecellsenter
circulation,butsoontoberenderedanergicorunresponsivebyother
mechanims).

Step 1: Selected people for the CBS show

(=selected useful T cells by epithelial cells)

Is this a positive or negative

selection?

Step 2: Selected persons are eliminated

(=eliminated harmful T cells by thymic dendritic cells)

Is this a positive or negative

selection?

The number of MHC molecules and size

of T cell repertoire
deletionratebynegativeselection

As the number (N) of MHC molecules

increases, the proportion of T cells that are
positively selected (= # of the cells that
survive) goes up arithmetically (N times),
while that of negatively selected (= # of
deleted cells) goes up geometrically (N2 times).
N= number of MHC isotypes a person
expresses
Therefore, the magic N to result in maximum T
cell repertoire is around 13.

Bonemarrowtransplantationtherapyinleukemiapatients

Figure 5-10

WhathappensifthereisacompletemismatchinMHCI/IITYPE?
Seethenextslide.

Figure 5-11

Whatyoulearnedatschoolshouldworkintherealworld!

Whathappensifyoudonothavethethymus?
DiGeorgessyndrome
NoorfewTcellsduetoverysmallornothymus
SymptomssimilartoSCIDpatients

Thymicinvolution:Thymusdegenerateswithage.
Ifyouareolderthan60,yourthymusistoosmalltoproduceT
cells.

Generation of nave T cells in thymus

T cell progenitors
TCR gene rearrangement

TCR

100%

notselectedbyMHCI/II

Blood

TCR
Selections for T cells that are MHCrestricted and not self reactive

2%

CD4orCD8TCRT cells

Generation of T cell clones:

clonality
G: TCR in germ line configuration
A, B, C: rearranged TCRs with different specificities

Stem cells

Thymus
TCR
recombination

Thymus
Selection for
The T cells
with good
TCR

Ag For
TCR A

A
A
A
C

Ag For
TCR B
Secondary
Lymphoid
tissues.
Ag-dependent
expansion of
clones.

C
C

Summaryof
Tcell
development
inthymus

Figure 5-18

Summaryof
Tcell
development
inthymus

Figure 5-19
Genes