CELL-MEDIATED

IMMUNE RESPONSES
IMMUNOLOGY SYSTEM

Department of Biochemistry
Faculty of Medicine UNHAS
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The Immune Response
(Animation)

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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 (MHC)
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Types of intracellular microbes combated by T cell-mediated
immunity

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• What signals are needed to activate
T lymphocytes?
• What cellular receptors are used to sense
and respond to the signals?
• How are the few naive T cells specific for
any microbe converted into the large
number of effector T cells that have
specialized functions and the ability to
eliminate diverse microbes?
• What molecules are produced by
T lymphocytes that mediate their
communications with other cells, such as
macrophages and B lymphocytes?
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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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Steps in the activation of T lymphocytes

Helper T
cell

Cytotoxic
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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 • CTLA (Cytotoxic
Lymphocyte-
associated
Antigen)
• LFA (Lymphocyte
Function
Associated
Antigen)
• VLA (Very Late
Activation)
• ICAM (Intercellular
Adhesion
Molecule)
• VCAM (Vascular
Cell Adhesion
Molecule)

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Ligand-receptor pairs involved in T cell activation
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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TCR-APC Interaction
(Animation)

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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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Regulation of integrin avidity

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Role of costimulation in T cell
activation

• The second signal

• 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)

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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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Signal transduction pathways in T lymphocytes

Production of cytokines, cytokine receptors, cell cycle inducers, and 22

effector molecules such as CD40L
TCR Signaling
(Animation)

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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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Cytokine
• A wide variety of intercellular regulatory
proteins produced by many different cells
in the body which ultimately control every
aspect of body defense.
• Cytokines activate and deactivate
phagocytes and immune defense cells,
increase or decrease the functions of the
different immune defense cells, and
promote or inhibit a variety of nonspecific
body 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

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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

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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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 Development of memory
T lymphocytes
• A fraction of antigen-activated T
lymphocytes differentiates into long-lived
memory cells
• Can be found in: lymphoid organs
(central memory cells), mucosal tissue
(effector memory cells), circulation
• Require signals from IL-7 and IL-15
• Waiting for the infection to return

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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
antigens, 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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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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