Download Mature T cells

Maimun ZA
1. Site of Lymphocyte Maturation
Lymphocyte arise from bone marrow-derive
precursor = hematopoetic cells
From pluripotent stem cells
The sites:
* B cells maturation
foetus  in liver
baby  in bone marrow.
* T cells maturation  in bone marrow 
migrate to thymus
Maturation of lymphocyte
Lymphocyte develope from precursors in the generative lymphoid organs
(the bone marror and thymus). Mature lymphocyte enter the peripheral
organs, where they respon to foreign antigens and from where they
recirculate in the blood and lymph.
2. General features of Lymphocyte maturation
Maturation stadium  genetic and cellular
changes
Early maturation:
Forming somatic recombination and receptor
gene. Receptor expression (for antigen)
“marker” +. B & T precursors are not well
defined by phenotype marker  can be
demonstrated by genetic abnormalities
Cell proliferation  induced by cytokines
The sequence of maturation:
• Stem cells  Pro lymphocyte  Pre
Lymphocyte  Immature Lymphocyte 
Mature Lymphocyte  Lymphocyte effector
(differenciated/spesific).
Gene Recombination Receptor and expression
The key event in lymphocyte maturation
For the generation of a diverse repertoir and processes
selective survival with useful specificities
B or T cell clons are produce antigen receptor
Gene recombination receptor
composed by somatic recombination
coded by gene
in a certain locus gene segment
forming from some DNA sequences
Molecular mechanism of Ig or TCR gene recombinations are
similar, functionaly, Ig only in B cells - TCR genes in T cells.
 Express on the surface cells, antigen receptors are
expressed before encounter with antigen.
Receptor expression on the surface cell
• As the result of gene recombination,
• Many immature limphocyte clons with
many receptor genes are formed
• Useful clones  positive selection
• Unuseful clones  negative selection 
programme cell death (apoptosis)
• Clones that fail to express receptor 
negative selection.
Receptor
Marker: Signal maker
Formed via gene recombination
Expressed on cell surface as antigen receptor.
B cells  B Cell receptor (BCR) 
Immunoglobulin (Ig)
T cells  T Cell Receptor (TCR).
Example:
Incomplete receptor (Pre-lymphocyte)
used: signal marker for the next maturation
process avoid lymphocyte from apoptosis.
Complete receptor (lymphocyte immature)
used: to give signal to survive, proliferation and
maturation. Unformed  programmed to cell
death (apoptosis)
3. Maturation Process
a. Early maturation
- Stem cells have been determined
(lymphocyte lineage)
- Several genes are involved in the maturation
process.
- Signed by high mitotic activity
- Some molecules are involved in this process,
such as:
– Cytokine  Interleukin-7 (Il-7),
– Membrane protein,
– Thymus stromal cells.
b. B lymphocyte maturation
The sequence begin from
arrangement of gene recombination
 Ig gene expression  immature
cells proliferation  selection of the
cells.
B cells maturation stadium
Need sequence stages:
Pro-B cell
• Not yet produced Ig,
• Differenciated from the other immature B
cells  CD19 and CD10 molecules expression.
Pre-B cell
• Incomplete Ig receptor
Not expressed Ig yet (antigen reseptor for B
cell)
• Receptor importancy  stimulate proliferation
and maturation  avoid from apoptosis.
• Next step  forming complete Ig complex 
expressed on the surface cell as IgM (IgMs)
Immature B lymphocyte
• IgMs
• Begin to form another complexes  IgM
and IgD.
Mature B lymphocyte
• IgMs and IgDs
• responsive to outer antigen
• Leaving bone marrow  peripheral
lymphoid tissue.
Sel B naive B cells
• Present in peripheral lymphoid tissue &
blood
• Not yet activated by antigen
• IgD+IgM+
NB:
• During B cells maturation  selection
process occurs (by self antigen-MHC), to
eliminate or non activate another B cell
precursor from unclear/unuseful clones.
Steps of B cells maturation
Steps in the maturation and selection of B lymphocytes . The maturation of B
lymphocytes proceeds through sequensial steps, each of which is characterized
by particular changes in Ig gene expression and in the patterns of Ig protein
expression. At the pro B cell and pre-B cell stages, failure to express functional
antigen receptors (Ig heavy chain and Ig light chain, respectively) resut in death
of the cells by default pathway of apoptosis.
c. T lymphocyte maturation
- Principally, occurs in bone marrow, similar with B
cell maturation.
- Thymus is the main site for T cells maturation.
T cell is called Thymocyte,
- Thymocytes, not yet mature  outher cortex
area, not expressed TCR yet,  move to cortex,
express TCRs  to medulla,  mature T cells
(CD4+ or CD8+)  peripheral lymphoid tissue or
blood.
T cells maturation stadium
Immature T cells in cortex thymus,
Pro-T cells or Double-negative thymocytes
• Not expressed TCR yet  CD4- or CD8Pre-T cells or Double-positive thymocytes
(T CD4+CD8+ cells)
• express CD4 and CD8
• Expression of CD4 or CD8 are important  ability to
respond to antigen.
• Pre-T cells then move to medulla
Mature T cells
• Express CD4+CD8‫ ־‬or CD8+ CD4 ‫־‬
• Single-positive thymocyte.
• Detected from the expression of CD4 or CD8
mol. (spesific).
• Specificity base on the function of 
- CD4+ T cells  produce cytokines that “help”
B cells and macrophage againts antigen
stimulation.
- T CD8+ cells has ability to produce molecules
that can dissolve other cells or regulate
antibody forming.
• Then the mature thymocyte single-positif
move to peripheral lymphoid tissue.
Steps of T cells maturation
The maturation of T lymphocyte in the thymus through sequential steps that are often
defined by the expression of the CD4 and CD8 coreceptors. The TCR β chain is first
expressed at the double-negative pre-T cell stage, and the complete TCR is expressed in
double-positive cells. Maturation culminates in the development of CD4+ and CD8+ single
positive T cells. As in B cells, failure to express antigen receptors at any stage leads to
apoptosis (programme cell death).
4. Selection Process that Shape The B and T
Lymphocyte Repertoires
• Positive selection
Lymphocytes are positively selected to
recognize peptide antigens displayed by
self MHC molecules  considered “self”
by immune system  escape from
apoptosis (programmed cell death).
Negative selection
Growing lymphocytes elimination in
conection with self-MHC 
lymphocytes are assumed not “self”
 programmed apoptosis.
• Growing lymphocyte (B and T)
sensitive to negative selection soon
after they express their receptors on
surface cells.
Lymphocytes  programmed to apoptosis
are:
(1) Functionaly fail to express useful antigen
receptor
(2) Receptors that are expressed do not
recognize ligands which induced positive
selection
(3) Immature lymphocytes are recognized by
self antigen with high avidity, or Immature
lymphocytes that strongly recognize self
antigen are negatively selected.
• Final result of maturation process above 
≤ 10% lymphocytes  move to blood and
lymph.
Selection process to T and B cells
Steps in maturation and selection of MHC-restricted T lymphocyte. During their
maturation, B and T lymphocytes go through cycles of proliferation and expression of
receptor chains by gene recombination. Cells that fail to express useful receptor die by
apoptosis, because they do not receive necessary survival signals. At the end od the
process, the cells undergo positive and negative selection.
T Lymphocytes
Characteristic  Phenotype is shown by the
marker molecules (CD4/CD8) that are expressed
on the surface membrane cell.
Functions:
- effector of cell mediated immunity
- regulator of immune respons
Subpopulation T lymphocyte
2 main subpopulations: CD4+ and CD8+ (2:1)
CD4+  (Activated by Antigen-MHC II complex)
- T helper  Subpopulation Th1 & Th2
- T regulator  TH1 dan TH2
CD8+  (Activated by Antigen-MHC I complex)
- Cytotoxic T Lymphocyte (CTL)
Steps in activation of T lymphocyte
Antigen recognation
Lymphocyte activation
Clonal expansion
& Differentiation
Effector functions
Steps in
activation of
T lymphocyte
Naive T cells recognize MHC-associated peptida antigens displayed on APCs + other signal
(not shown). The T cells respond by producing cytokines, such as IL-2, and expresing
receptors for these cytokines, leading to an autocrine pathway of cell proliferation. The
result is clonal expansion of the T cells. Some of the progeny differenciate into effector
cells, which serve various functions of cell-mediated immunity, and memory cells, which
survive for long periods.
The role of
costimulator in
T cells
activation.
Naive T cells that have recognized antigen without costimulation may become
unresponsive to subsequent exposure to antigen, even if costimulations are
present  anergy. Microbes, and cytokines produced during innate immune
responses to microbes, induce the expression of costimulation, such as B7
moleculs, on the APCs. The B7 costimulators are recognized by the CD28
receptor on naive T cells, providing “signal 2” and in conjunction with antigen
recognition (“signal 1”). The recognition initiates T cell responses.
Activation
The molecules that are involved
in T cell activation
Antigen Presenting Cell (APC):
peptide-MHC II complex.
B7 mol, Cytokines (costimulator)
CD4+ T cell:
TCR
CD4 mol (coreceptor)
CD3, , CD28 molecules (costimulator)
Effector function of CD4+ T cell
CD4+ T cells that have
differentiated into effector
cells express CD40L and
secrete cytokines. CD40L
binds to CD40 on macrophages or B lymphocytes,
and cytokines bind to their
the receptor on the same
cells. The combination of
signals delivered by CD40
and cytokine receptors
activates macrophages in
cell-mediated immunity
(A) and activates B cells to
produce antibodies in
humeral immune
responses (B).
Activation of CD8 Tcells
A). In some interactions, APCs may ingest
infected cells and present microbial
antigens to CD8+ T cells and to CD4+
helper cells. The helper cells then produce
cytokines that stimulate the expansion
and differentiation of the CD8+ T cells. It is
also thought that helper cells may activate
APCs to make them competent at
stimulating CD8+ T cells (not shown).
B). CD8+ T cells recognise class I MHCassociated peptides and receives
costimulatory signal if a profesional APC
harbors a cytoplasmic microbe.
Development of Memory T Lymphocyes
A fraction of antigen-activated T lymphocytes
defferenciates into long-lived memory T cells.
• Memory cells survive even after the infection is
eradicated
• They can be found in lymphoid tissue, in
mucosal barriers, and in the circulation.
• Memory T cells do not continue to produce
cytokines or kill infected cells, but they do so
rapidly on encountering the antigen that they
recognize. Thus, memory cells are pool of
lymphocyte waiting for the infection to return.
B cell Lymphocytes
Function:
Secreting antibody  plasmacyte
APC professional
Marker on surface cell:
Imunoglobulin (M), MHC-I, MHC-II, IL-2
R, transferin, receptors, CD19, CD20,
CD21, CD22, CD23, CD37, CD39, CD40
and CD45. (Kishimoto, T and Hirano, T,
1989).
B cells activation
2 kinds: Direct & Indirect activation
• Direct activation of B cell is stimulated
by:
Type 1 thymus independent antigens 
polyclonal antigen activators  IgsR on
spesific B cells.
Type 2 thymus independent antigens
(polymeric molecules)  crossreaction
with many IgsR  long live  a sustain
signal to B cells  forming antibody.
B-cell recognition of (a) type 1 and (b) type 2
thymus-independent antigens.
• The complex gives a sustained signal to the B-cell
because of the long half-life of this type of molecule.
a/ activation signal; surface Ig receptor; b/ crosslinking of receptors.
Indirect B cells activation
• Thymus dependent antigens 
cooperate with T-helper 
activate resting/naive B cells.
(see also CD4 Tcell activation)
The Role of B cells
• Signal from Ag.
T independent Ag: B cells (via IgsR) 
cross-linking  the growth &
differentiation (helped by other
signals)  Plasmacyte  produce
antibody.
T dependent Ag: professional APC 
present antigen-MHC II complex  to
CD4 Tcell  CD40L  produce IL-4 &
IL-6  B cells  Plasmacyte 
Antibody Forming Cell (AFC).
Development of Memory B
Lymphocytes
Similar with The Development of
Memory T Lymphocytes
Classes of lymphocyte
Note:
T limphocytes recoqnize peptides that
are displayed by MHC molecules
Different classes of limphocytes
recoqnize distinc types of antigens
and differentiate into effector cels
whose function is to eliminate the
antigens.
B lymphocytes recognize soluble
or cell surface antigens and
differentiate into antibodysecreting cells.
Helper T limphocyte recoqnize
antigens on the surface of
antigen-presenting cells and
secrete cytokines. Which
stimulate different mechanisms of
immunity and inflamation.
CT L recoqnize antigens on
infected cells and kill these cells.