1. Lymphocytes
Trafficking & T-
Cell Response
Dr Alok Tripathi
Department of Biotechnology
aquaimmuno@yahoo.co.in

2. T Cell-Mediated Immunity
Headings
• T Cell Activation
• Properties of Effector T Cells
• Cytotoxic T Cells
• Macrophage Activation by Th1
(Inflammatory T) Cells
This Presentation
will help you
see how T cells are
activated by
antigen presented
on APC.
understand the
properties and
functions of
effector T cells.

3. Headlines in Nutshell
Singling between APC & T
cells depends upon CAMs
CAMs allow them to come
closure, so that Ag specific
interaction can occur, if it
would be!
After this adhesion, MHC-
peptide & TCR come closure
to bind up
This is further facilitated by
LFA-1 for more strong
binding
Meanwhile, T cell, in complex,
starts dividing & daughter
cells remain attached to them
& receive activation signal.

4. Self-MHC restriction of the T-cell receptor
(TCR). A particular TCR is specific for both an
antigenic peptide and a self-MHC molecule.

5. I. Importance of T lymphocytes
Both T and B cells are needed to generate an Ab response
Helper T cells activate B cells to produce Ab
CTC are the other type of T cell, which actively kill other
cells
T cells are clonally selected via Ag recognition by the T cell
receptor
T cell Ag recognition is similar (e.g. TCR, Ig are
homologous) to that in B cells, but distinct in mechanism
T cells develop in the thymus (this is the principle function
of this organ)

6. Effector Cells in Adaptive Immunity
Effector
T Cell
Pathogen
Location
Antigen
Presentation
Target Cell
Action
Cellular
Immunity
Tc CD8
cytotoxic
Cytoplasm
Infected cell
MHC I
Infected cell
apoptosis
Th1 CD4
inflammatory
Macrophage
vesicles
Macrophage
MHC II
Macrophage
activation to
kill pathogen
Humoral
Immunity Th2 CD4
helper
Extracellular APC MHC II
B cell antibody
production

7. T Cell Activation
Adaptive T cell-mediated
immunity is driven by
activation of T cells:
cytotoxic T cells activated by
endogenous antigen to
kill infected cells,
helper T cells activated by
exogenous antigen to
stimulate MΦ killing of
endosomal pathogens.
Adaptive humoral immunity
also usually involves T cell
activation to produce
cytokines that stimulate B
cell antibody synthesis.

8. T Cells Recognize Ag by a Unique Mechanism
T cells recognize linear 9-10 aa
peptide sequences
T cells only recognize Ag’s
presented on the surfaces of APC
MHC restriction: the MHC allele
expressed on the APC must be
correct to stimulate T cells

9. Major Histocompatibility Complex
(A) Discovery of the MHC
discovered by mapping cell surface antigen
responsible for tumor graft rejection
the surface antigen is the MHC, recipient
and donor must have matching MHC’s for
graft to be accepted
the MHC is called H-2 in mice and HLA in
humans

10. Major Histocompatibility Complex
The MHC locus encodes three classes of molecules
MHC
Class I
Dimer of  chain and 2m
(not in locus)
Three types, HLA A, B, C (in
mouse, H-2K, -2D, -2L)
Expressed on all cell surfaces
except neurons and RBC
Special subclass Ib is
nonpolymorphic and tissue
specific, related to bacterial
pathogen response
MHC
Class II
Heterodimer of  and 
chains
Three types DP, DQ, DR (in
mouse I-A, I-E)
Only expressed on APC’s
MHC
Class III
related to complement and
cytokines, irrelevant to this
topic

11. MHC genes are highly polymorphic
polymorphism in HLA genes for both
class I and II is “balanced”
nomenclature: HLA A*(allele #) (in
mouse, superscript is allele type)
most variation is localized to Ag
binding domains (1 2 in class I, 1
1 in class II

12. MHC restriction is mediated by specific
recognition by the TCR
T cells are activated only if APC expresses
the correct MHC
Can test which MHC is responsible directly
(correlate genotypes with response) or by
specific blocking with antibodies
Only one TCR needed to recognize both Ag
and MHC

13. IV. The T Cell Receptor
Discovered by clonotypic Ab and subtractive
hybridization
The TCR is made of two chains,  , similar to Ig;
each have one variable and one constant region
TCR gene rearrangement
 rearranges by VJ,  by VDJ
using the RAG’s
junctional diversity is important
but hypermutation is not

14. How Ag is recognized
APCs must process antigen before recognition occurs (hence, a
time lag)
MHC molecules bind a single, short Ag peptides of 9-10 aa (not
TCR!)
MHC molecules are specific in binding only certain peptides
Complexity of immunogens and diversity of MHC expressed
allows response to lots of pathogens, but susceptibility varies
with MHC genotype
The 1 and 2 domains of MHC form a catcher’s mitt with a
groove to bind peptides; anchor positions give great specificity
at those residues

15. Model for Ag Recognition by T Cells
Uptake of Ag by APC
Processing of Ag (proteolysis)
Presentation of Ag peptide fragment
on MHC
Recognition of MHC-Ag complex by
T cells (this is MHC restricted)

16. VII. T Cell Subsets
Two classes
of T cells
1) CD4+
Recognize exogenous Ag on MHC II on
APC’s
Release cytokines (IL2  T cell
proliferation, IL4,5,6  B cell
activation)
Ag taken up by endocytosis, cleaved in
lysosome
For B cells, Ag binding to surface Ig
results in rapid uptake of Ag
Invariant chain (Ii) blocks MHC II
binding site until fusion with lysosome
2) CD8+
Recognize endogenous (viral) Ag
on MHC I on all cells (except
neuron, RBC)
Cause cytolysis of infected cell
Viral proteins cleaved by
protesome, enters ER through
TAP1/2 transporters

17. VIII. T cell/APC interaction
The CD’s interact specifically
with their MHC; also coupled
to signaling pathway (lck)
Interactions between
accessory proteins are
required for T cell activation
Superantigens (e.g. some
bacterial endotoxins)
promote T cell activation by
binding TCR and MHC
outside of cleft
huge number of T cells
activated eventually lead to
toxic shock syndrome
IX. Other
Ag specific T cells can be
detected with labeled MHC or
MHC-Ig molecules
HIV coat protein gp120 binds
CD4, first step in virus infection

18. Key Adhesion Molecules in T-Cell Activation
Ig Superfamily
Adhesion Molecule
Tissue Distribution Integrin Legend
CD2 (LFA-2) T cells LFA-3 on APC
ICAM-1 (CD 54)
Activated endothelium
dendritic cells
T cells
LFA-1 on T cells
MAC-1 on macrophages
ICAM-2 (CD102) Resting endothelium LFA-1 on T cells
ICAM-3 (CD50) Naïve T cells
DC-SIGN on dendritic
cells
LFA-3 (CD58)
Lymphocytes
APC
CD2 on T cells

19. CD40
P
→
mIgM & mIgD
APC
Ÿ
← TCRs
Ag
MHC-II
CD40L
IL2,IL4, IL10,
IL5, & IFN γ
B7 & CD28

20. TCRs-PEPTIDE-MHC COMPLEX

21. Kill
Endogenous
Antigen
Activate
CTL
Kill Infected
Cell
Exogenous
Antigen
Activate
Th
Stimulate
Mᶲ
Endosomal
Pathogens

22. Naïve
T Cell
MHC-I~Peptide
CD-8
T
Cell
MHC-II
CD-4
T
Cell
Co-Stimulatory Signals
APC
Only professional APC
(DC, NK & B- Cells )
have both MHC-I;II
and can deliver co-
stimulatory signal
Proliferate &
Differentiate
Perform their function
when they encounter
Target cell-
MHC~peptide

23. APC [B-Cell]
Th
Y
Ag
MHC-II P
B7 CD-28
TCR
CD-40 CD-40L
CK
CO-STIMULATORY SIGNALS
Nucleus
Singling
Cascades

24. Lymphocytes Trafficking
Definition: “Trafficking of lymphocytes
between tissue, the blood stream and lymph
nodes enable antigen sensitive cells at which
response is occurring”
Recognisation of vascular adressins on vascular
endothelium in secondary lymphoid organ

25. Mechanism of T cell
Activation

26. As the T-Cells Adhere to
APC
Movements of TCR towards
the Peptide~MHC Starts
They come closure to each
other and bind
Thus the complex so formed
will be [T-CELLS-TCR-
PEPTIDE~MHC-APC]
• LFA-1 changes its confirmation
Binding become tighter
• This is required for the long time
to Activate the cells
After the receiving
stimulation signal T cells
starts dividing and its
progeny still attached to the
mother cells and received
activation signals
To activate the T cells APC
has to delivered two signals
• To TCR via MHC~Peptide
Complex
• Co-stimulatory signal via
interaction of B7 to CD-28

27. In general the same cell must delivered the antigenic and co-stimulatory signal
simultaneously for the activation of the T cell.
• Not all self reactive T cells are deleted in the Thymus
• Since some self antigens are appropriate in the other
tissues
This is because :
Now if Ag & Co-stimulatory signal could be delivered separately, T cells could
be stimulated by SELF PEPTIDE on Non APC & become fully activated to
make an auto immune response by an APC presenting different peptide
The T cells which binds to Ag and couldn’t get co stimulatory signal become
ANERGIC and can't responds in future even if proper co stimulation is
received
Why these cells are inactivated without killed is not known !!!!!!!!!!!
APC=DC,Mᶲ or B cells:
DC deliver both signal and are the best
APC and are the responsible for the
activation of the most of the naïve cells

28. CD-40L
T-Cells
Ag & Co-Stimulatory
Signals
Activated
T Cells
Express
Other
receptors
Enhance Co
stimulation
APC
CD-40
To provide
more co
stimulation
Express More B7
molecules
To send activation
signals to T cells
Activate
M &
B- Cells
Further Interaction of APC & T Cells

29. The immune response therefore depends upon PUSH of the
antigen stimulation to activate T cells in to effectors cells and
PULL of negative signal that curtail T cells response
B7CTAL-4
ICOS
4-IBB/CD-137 4-1BBL
To further activate T &
APC
LICOS
Inducible co stimulator
Binds 20 times more
avidly then CD-28 send
activation signals