9 - Biology of T-cells, TCR, 2018

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Biology of T-cells, TCR, and
antigen presentation
Dr.Eman Albataineh,
Associate Prof. Immunology
College of Medicine, Mutah university
• T cells involved in defense against
intracellular and extracellular pathogens (
cell mediated immunity and help in
humoral immunity)
• Tumor immune response
• allograft rejection
• Regulation of Ab production
αß T cells
• About 90-95% of the blood T cells
• The receptor has two polypeptide chains α
and ß
• Besides TCR is CD coreceptor
– CD4+ = (Th)
– or CD8+ = (Tc)
αß TCR
• Complete TCR is the αß
receptor plus CD3
• Each chain constitute of
one variable, one
constant, hinge,
transmembrane and
cytoplasmic tail
• Hypervariable regions on
both Vα and Vß are the
same as those of
antibody located on Agbinding site and called
CDR and they are 3 sites
for each
CD4 and CD8
• Cluster of differentiation (CD) are proteins expressed on
T cells (CD4 or CD8), also they called co-receptors,
have a role in binding the MHC and antigen and used to
differentiate T cells by binding to monoclonal antibodies.
CD8 T cells are Tc, CD4 T cell is Th1 or Th2
• Immunoglobulin superfamily also includes the antigen
receptors of T and B cells, the co-receptors CD4, CD8,
and the domains of MHC molecules.
• Lymphocytes specific for a large number of
antigens exist before exposure to the antigen,
and when an antigen enters a secondary
lymphoid organ, it binds to (selects) the antigenspecific cells and activates them.
• This fundamental concept is called the clonal
selection hypothesis.
• The activation of naive T lymphocytes requires
recognition of peptide-MHC complexes
presented on antigen presenting cells (APC)
Requirement for T cell activation
• Specific ligand on the appropriate MHC molecule
(signal1)
• Co stimulatory molecules (signal 2) mainly CD28
• Signal 3, cytokine effect; T cells proliferation by the effect
of IL-2 growth factor from DC to act on T cell, and from T
cell to act on itself
• If one of the first 2 is absent-----T cell anergy and
tolerance
• If both present-------T cell proliferation and differentiation
to effecter and memory cells
– Effecter cell in CD8 cells is always cytotoxic T lymphocyte (CTL).
– Where as effecter CD4 T cells might be TH1 or TH2 cells.
T cell costimulatory molecules for
binding
• Enough Naïve CD4&8 cell activation need binding of T cell with APC by:
CD4/8 cell---APC
1- TCR/CD3---antigen +MHC (CD3 signal for TCR aggregation)
2-CD4/8---MHC2/1
And accessory or costimulatory molecules
1- CD28---B7 (CD80/86)(immunoglobulin super family, signal for costimulation and production of IL2 for T cell survival and proliferation,)
2- LFA-1---ICAM-1&2
3- CD40L---CD40 ( important for activation and isotype switch of B cells,
increase expression of IL-12 by DC)
4- ICAM-3----DC-SIGN (specific to DC)
costimulatory molecules on T
cells
Activated cells
• Activated CD4+ helper T lymphocytes proliferate and
differentiate into effector cells whose
functions are mediated largely by secreted cytokines. For
example; interleukin-2 (IL-2), which is a growth factor that
stimulates the proliferation (clonal expansion) of the
antigen-specific T cells.
• Activated CD8+ lymphocytes proliferate and differentiate
into CTLs that kill cells harboring microbes in the
cytoplasm. These microbes may be viruses that infect
many cell types or bacteria that are ingested by
macrophages but escape from phagocytic vesicles into
the cytoplasm (where they are inaccessible to the killing
machinery of phagocytes, which is largely confined to
vesicles). By destroying the infected cells, CTLs
eliminate the reservoirs of infection
APCs
• Antigen-presenting cells are
distributed in tissues, blood and
in the lymph node
• Dendritic cells, Macrophages and
B cells
• Mature dendritic cells are by far
the most important activators of
naive T cells and activated by
wide range of antigens (viral.
Bacterial and allergens)
• B cell bind soluble intact antigen
and present it to TH by MHC2
• Immature dentritic cells,
exist at tissues and sites of
infection, they express
MHC1 & 2 and phagocytic
receptor PRR, but low
adhesion molecules.
• Internalization occur as a
result of binding the Ag
with PRR or by
macropinocytosis.
• After engulfing the
pathogen they become
mature DC; migrate to
peripheral L.N.
– lose their phagocytic activity
– and express more adhesion
molecules, MHC and costimulatory molecules,
– secret chemotactic factors to
attract naïve T cells to the LN.
• Surface immunoglobulin (IGM or IGD) allows B cells to bind and
internalize specific soluble intact antigen very efficiently. The
internalized antigen is processed in intracellular vesicles where it
binds to MHC class II molecules. These vesicles are then
transported to the cell surface where the MHC class II:antigen
complex can be recognized by Th2 cells. Because of high
specificity, it is perfect when Ag concentration is low.
T cells costimulatory molecules functions
– CD28, the earliest accessory molecules induce
signaling after TCR CD4/8 binding to MHC and
antigen it initiate T cell proliferation by expression of
IL-2 cytokine and its receptor. CTLA-4 is expressed in
stead when the antigen is cleared So that T cell is
regulated
– CD40L that bind CD40 on B cells that lead to B cells
activation
Inappropriate Ag or MHC
• CD4 bind MHC2 and
CD8 bind MHC1
• TCR bind both the Ag
and part of MHC
• Self Ag result in
immature DC and
macrophages (no costimulatory
molecules)….T cell
anergy.
In appropriate T cell activation;
T cell stimulation by Super antigens
• Super antigens; are a class of antigens which cause non-specific
activation of T-cells resulting in and massive cytokine release from
macrophages
• Causes; staphylococcal enterotoxins and streptococcal M protein,
Others include EBV and HIV.
• Pathology; Bind in-appropriately to the outer part of Vß domain of
the TCR and to outer part of MHC 2 and cause activation of massive
no. of T cells and huge amount of produced cytokines, as the
frequency of T cells that have Ag specific Vß domain is higher than
to have both Ag specific Vα and Vß TCR (10% : 0.01%)
• Immunological effects; increase in IL1, TNF alpha and IL2 as a
result of increased macrophage activation by T cells….fever,
massive vascular leakage and shock.
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