CELL-MEDIATED

IMMUNE RESPONSES

Faculty of Medicine UNHAS

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Contents
• Introduction
• Phases of T Cell Responses
• Antigen Recognition and Costimulation
• Recognition of MHC-associated Peptides
• Role of Adhesion Molecules in T Cell Responses
• Role of Costimulation in T Cell Activation
• Stimuli for the Activation of CD8+ T Cells
• Biochemical Pathways of T Cell
Activation

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Contents
• Functional Responses of
T Lymphocytes
• Antigen and Costimulation
• Secretion of Cytokines and Expression of
Cytokines Receptors
• Clonal Expansion
• Differentiation of Naive T Cells into
Effectors Cells
• Development of Memory T Lymphocytes
• Decline of the Immune Respons
• Summary

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Introduction
• Cell-mediated immunity
• Adaptive immune response
• Combat infections by intracellular microbes
• Mediated by T lymphocytes
• Help B cells to produce antibodies
• Interactions between T lymphocytes and
phagocytes, infected host cells, or B
lymphocytes
• Can see and respond to only antigens
associated with other cells → major
histocompatibility complex (MCH)
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 Types of intracellular
microbes combated by
T cell-mediated
immunity

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Phases of T Cell Responses
• The responses of T lymphocytes to cell-
associated microbial antigens consist of
a series of sequential steps that result in
an increase in the number of antigen-
specific T cells and the conversion of
naive T cells to effector cells

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 Helper T
cell

Steps in the activation of Cytotoxic

T lymphocytes T cell

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Antigen Recognition and
Costimulation
• The initiation of T cell responses
requires multiple receptors on the T cells
recognizing ligands on APCs
• The TCR recognizes MHC-associated
peptide antigens
• CD4 or CD8 co-receptors recognize the MHC
molecules
• Adhesion molecules strengthen the binding of T cells
to APCs
• Receptors for costimulators recognize second signals
provided by the APCs

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Ligand-receptor pairs involved in T cell activation 12
Recognition of major histocompatibility
complex-associated peptides

• The T cell receptor for antigen (the TCR) and

the CD4 or CD8 co-receptor together recognize
the complex of peptide antigens and MHC
molecules on APCs, and this recognition
provides the first, or initiating, signal for T cell
activation
• The biochemical signals that lead to T cell
activation are triggered by a set of proteins that
are linked to the TCR to form the TCR complex
and by the CD4 or CD8 co-receptor

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 Antigen recognition
and signal transduction
during T cell activation

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Role of adhesion molecules in
T cell responses

• Adhesion molecules on T cells

recognize their ligands on APCs and
stabilize the binding of the T cells to the
APCs
• Integrins play an important role in
enhancing T cell responses to microbial
antigens

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 Adhesion
molecules involved
in leukocyte
interactions

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Regulation of integrin avidity

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Role of costimulation in T cell
activation

• The full activation of T cells is

dependent on the recognition of
costimulators on APCs
• B7-1 (CD80), B7-2 (CD86) – CD28
• CD40 – CD40L (CD154)
• Example: adjuvant
• Proteins homologous to CD28 also are
critical for limiting and terminating
immune response
• CTLA-4

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 The role of
costimulations in T
cell activation

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Stimuli for the activation of CD8+
T cells

• The activation of CD8 T cells is

stimulated by recognition of class I
MHC-associated peptides and requires
costimulation and/or helper T cells

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Activation of CD8+ T cells
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Biochemical Pathways of T Cell
Activation
• On recognition of antigens and
costimulators, T cells express proteins that
are involved in proliferation, differentiation,
and effector functions of the cells
• The biochemical pathways that link antigen
recognition with T cell responses consist of
the activation of enzymes, recruitment of
adapter proteins, and production of active
transcription factors

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Proteins produced
by antigen-
stimulated T cells

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 Functional Responses of
T Lymphocytes to Antigen and
Costimulation
• The recognition of antigen and costimulators
by T cells initiates an orchestrated set of
responses that culminate in the expansion of
the antigen-specific clones of lymphocytes
and the differentiation of the naive T cells into
effector cells and memory cells
• Many of the responses of T cells are
mediated by cytokines that are secreted by
the T cells and act on the T cells themselves
and on many other cells involved in immune
defenses.
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Secretion of cytokines and
expression of cytokine receptors

• In response to antigen and

costimulators, T lymphocytes, especially
CD4+ T cells, rapidly secrete several
different cytokines that have diverse
activities

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Properties of the
major cytokines
produced by
CD4+ helper T
lymphocytes

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 The role of
interleukin-2 (IL-2)
and IL-2 receptors
in T cell
proliferation

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Clonal expansion
• Within 1 or 2 days after activation, T
lymphocytes begin to proliferate,
resulting in expansion of antigen-specific
clones

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Differentiation of naive T cells into
effector cells

• CD4+ helper T cells differentiate into

effector cells that respond to antigen by
producing surface molecules and
cytokines that function to activate
phagocytes and B lymphocytes

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The molecules involved in the effector functions of
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CD4+ helper T cells
Differentiation of naive T cells into
effector cells
• CD4+ helper T cells may differentiate
into subsets of effector cells that
produce distinct sets of cytokines and
perform different functions

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 The development
and characteristics
of subsets of
CD4+ helper T
lymphocytes

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Differentiation of naive T cells into
effector cells

• TH1 cells stimulate phagocyte-mediated

ingestion and killing of microbes, a key
component of cell-mediated immunity

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The functions of TH1 cells 34
Differentiation of naive T cells into
effector cells

• TH2 cells stimulate phagocyte-

independent, eosinophil-mediated
immunity, which is especially effective
against helminthic parasites

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 The functions of TH2 cells

The functions of TH2 cells 36

Differentiation of naive T cells into
effector cells

• TH17 cells secrete the cytokines IL-17

and IL-22 and are the principal
mediators of inflammation in a number
of immunologic reactions
• The development of TH1, TH2, and TH17
subsets is not a random process but is
regulated by the stimuli that naive
CD4+ T cells receive when they
encounter microbial antigens
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The development of TH1 effector cells
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The development of TH2 effector cells
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Differentiation of naive T cells into
effector cells

• CD8+ T lymphocytes activated by

antigen and costimulators differentiate
into CTLs that are able to kill infected
cells expressing the antigen

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 The three main
types of armed
effector T cells
produce distinct
sets of effector
molecules

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Development of memory
T lymphocytes
• A fraction of antigen-activated T
lymphocytes differentiates into long-lived
memory cells

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 Encounter with
antigen
generates T cells
and long lived
memory T cells

The cells can differentiate into

different types of memory cells 43
 The components
of the three
phases of the
immune response
againts different
classes of
microoorganism

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Decline of the immune response
• Once an infection is cleared and the stimuli for
lymphocyte activation disappear, many of the
cells that had proliferated in response to
antigen are deprived of the survival signals
antigen, costimulatory signals from CD28, and
cytokines such as IL-2
• As a result, these cells die by a process of
apoptosis (programmed cell death)
• The response subsides within 1 or 2 weeks
after the infection is eradicated, and the only
sign that a T cell-mediated immune response
had occurred is the pool of surviving memory
lymphocytes.
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Summary
• T lymphocytes are the cells of cell-
mediated immunity, the arm of the
adaptive immune system that combats
intracellular microbes
• The responses of T lymphocytes consist of
sequential phases
• T cells use their antigen receptors to
recognize peptide antigens displayed by
MHC molecules on antigen-presenting
cells

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Summary
• T lymphocytes are the cells of cell-
mediated immunity, the arm of the
adaptive immune system that combats
intracellular microbes
• Antigen recognition by the TCR triggers
signals that are delivered to the interior of
the cells by molecules associated with the
TCR (the CD3 and ζ chains) and by the
co-receptors, CD4 and CD8, which
recognize class II and class I MHC
molecules, respectively

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Summary
• The binding of T cells to APCs is
enhanced by adhesion molecules
• APCs exposed to microbes or to cytokines
produced as part of the innate immune
reactions to microbes express
costimulators that are recognized by
receptors on T cells and deliver necessary
"second signals" for T cell activation

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Summary
• The biochemical signals triggered in T
cells by antigen recognition and
costimulation result in the activation of
various transcription factors that stimulate
the expression of genes encoding
cytokines, cytokine receptors, and other
molecules involved in T cell responses
• In response to antigen recognition and
costimulation, T cells secrete cytokines, of
which some induce proliferation of the
antigen-stimulated T cells and others
mediate the effector functions of T cells
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Summary
• CD4+ helper T cells may differentiate into
subsets of effector cells that produce
restricted sets of cytokines and perform
different functions
• CD8+ T cells recognize peptides of
intracellular (cytoplasmic) protein antigens
and may require help from CD4+ T cells to
differentiate into effector CTLs

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References
• Abbas, A.K., Licthman, A.H.: Basic
Immunology, 3th edn. Philadelphia,
Saunders Elsevier, 2009
• Janeway, C.A., Travers, P., Walport, M.,
Shlomchick, M.J.: Immunobiology, 6th
edn. New York, Garland Science, 2005

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NOTICE:
• ζ chain → δ chain
• IFN-γ → IFNγ
• Cγ (PLCγ) → Cγ (PLCγ)
• Ras•GTP and Rac•GTP →
Ras·GTP and Rac·GTP
• NF-κB → NF-κβ
• IκB → Iκβ
• PKCÎ → PKCθ
• TGF-β → TGFβ

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 Signal
transduction
pathways in
T lymphocytes

Production of cytokines, cytokine receptors, cell cycle

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inducers, and effector molecules such as CD40L