Development of cell mediated

immune response(CMIR)

Dr.D.RATHNAMMA
Professor and Head
Dept. of Veterinary Microbiology, Veterinary
College, KVAFSU, Hebbal, Bengaluru-560 024
• Humoral immune response: Effectors of the
humoral immunity are secreted antibodies, highly
specific molecules that can bind and neutralize
antigens on the surface of cells and in the
extracellular spaces. The primary domain of
antibody protection lies outside the cell.
• Cell mediated immune (CMI) response:
• Principal role of CMI is to detect and eliminate
cells that harbour intracellular pathogens.
• Cell mediated immunity can also recognize and
eliminate cells, such as tumour cells, that have
undergone genetic modifications so that they
express antigens not typical of normal cells.
• Cell mediated immunity consists of both helper T cells
(TH1) and several types of cytotoxic cells.
• Effector cytotoxic cells arise from both the adaptive
and innate immune systems and, therefore, include
both antigen specific and non specific cytotoxic cells.
• Antigen non specific (innate immunity) cytotoxic cells
that contribute to the clearance of target cells include
NK cells and non lymphoid cell types such as
macrophages, neutrophils, and eosinophils.
• Antigen specific cytotoxic cells include CD8+ T
lymphocytes (TC cells), as well as the CD4+ NKT cells,
which, although derived from the T-cell lineage,
displays some useful features of innate immune cell
type.
• Cytotoxic T lymphocytes (CTL), Natural killer T
(NKT) , and Natural killer (NK) effector cells all
induce cell death by triggering apoptosis in
their target cells.
• Cytotoxic cells eliminate cells infected with
intracellular pathogens (virus and bacteria),
tumor cells and cells that have been stressed
by extreme temperatures or trauma.
• Cytotoxic T lymphocytes, or CTLs, are
generated by immune activation of T cytotoxic
(TC or CD 8+T) cells. These effector cells have
lytic capability and are critical in the
recognition and elimination of altered self-
cells (e.g., virus-infected cells and tumour
cells)
• Naive TC cells are incapable of killing target
cells and are therefore referred to as CTL
precursors (CTL-Ps) to denote their
functionally immature state. CTL-P has to be
activated to differentiate into a functional CTL
with cytotoxic activity.
 Phases of Immune response
• Generation of specific immune response (HIR or
CMIR) that takes place after antigen stimulation
can be divided into three phases;
1. Recognition phase: lymphocytes recognize
antigen through their receptors and bind to antigen
2. Activation phase: proliferation and differentiation
of antigen activated lymphocytes.
3. Effector phase: Elimination of antigen by effector
cells (Plasma cells in HIR and CTL in CMIR).
During development of CMIR, endogenous / intracellular
antigens are processed and presented along with MHC class I
molecules. Antigen+MHC class I recognized by Tc cells (CTL-Ps).
Generation of CTLs from CTL-Ps appears to require at
least three sequential signals;
• An antigen-specific signal 1
is transmitted by the TCR
complex upon recognition of
peptide-MHC class I
complex.
• A co-stimulatory signal
(signal 2) transmitted by the
interaction of CD28 of CTL-P
and B7 of the infected cell.
• Signal induced by the
interaction of IL-2 with the
high-affinity IL-2 receptor,
resulting in proliferation and
differentiation of the
antigen-activated CTL-P into
effector CTLs
Generation of effector CTLs
Upon interaction with antigen+ MHC class I complexes on
appropriate target cells, CTL-Ps begin to express IL-2 receptors
(IL-2R) . Proliferation and differentiation of antigen-activated
CTL-Ps generally require IL-2 secreted by TH1 cells resulting from
antigen activation and proliferation of CD4+ T cells. In the
subsequent effector phase, CTLs destroy specific target cells.

Cytokines from TH1 cells

also regulate activation of
non specific effector
cells; NK cells and
Macrophages
 CTL mediated killing of target cell:
Primary events in CTL-mediated killing; conjugate formation,
membrane attack, CTL dissociation, and target cell destruction.
1. Directional delivery of cytotoxic proteins (perforin, a pore forming
protein and granzymes/ fragmentins, serine proteases) that are
released from CTLs and enter target cells.
2. Interaction of the membrane-bound Fas ligand on CTLs (death ligand)
with the Fas receptor on the surface of target cells.
• Either of these initiating events results in the activation of a signalling
pathway that culminates in the death of the target cells by apoptosis.

Within 5 min. of CTL contact,

target cell begins to exhibit
DNA fragmentation.
Destruction of target cells by NK cells:
• Natural killer cells appear to kill tumor cells and virus
infected cells by processes similar to CTLs.
• NK cells bear FasL on their surface and readily induce
death in Fas-bearing target cells.
• Cytoplasm of NK cells contains numerous granules
containing perforin and granzymes. Unlike CTLs, which
need to be activated before granules appear(CTL-Ps
lack cytoplasmic granules and perforin; upon
activation, cytoplasmic granules appear, MHC
restricted), NK cells are constitutively cytotoxic, always
having large granules in their cytoplasm. Release the
granule contents, perforin causes pores on the
membrane, granzymes induces death of target cells
 NK cells mediate Antibody dependent cell mediated
cytotoxicity (ADCC)
Among the cells that can mediate
ADCC are NK cells, macrophages,
monocytes, neutrophils, and
eosinophils, express membrane
receptors for the Fc region of the
antibody molecule. When antibody is
specifically bound to a target cell,
these receptor-bearing cells can bind
to the Fc region of antibody, and thus
to the target cells, and subsequently
cause lysis of the target cell.
Although these cytotoxic cells are
non specific for antigen, the
specificity of the antibody directs
them to specific target cells.
• Target cell killing by ADCC appears to involve a number of
different cytotoxic mechanisms, but not complement
mediated lysis.
• When macrophages, neutrophils, or eosinophils bind to a
target cell by way of the Fc receptor, they become more
active metabolically; as a result, the lytic enzymes in their
cytoplasmic lysosomes or granules increase.
• Release of these lytic enzymes at the site of the Fc mediated
contact may result in damage to the target cell.
• In addition, activated monocytes, macrophages, and NK cells
have been shown to secrete tumor necrosis factor (TNF),
which may have a cytotoxic effect on the bound target cell.
• NK cells and eosinophils contain perforin in cytoplasmic
granules, their target-cell killing also may involve perforin-
mediated membrane damage similar to the mechanism by
CTL-mediated cytotoxicity.
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