Killer cells, including natural killer (NK) cells and cytotoxic T cells, play an important role in the immune system by killing tumor cells and cells infected by viruses. NK cells are lymphocytes of the innate immune system that recognize and kill aberrant cells through surface receptors. Cytotoxic T cells are lymphocytes that express both T cell receptors and NK cell receptors, and kill infected cells through secretory lysosome exocytosis and release of cytotoxic granzymes and perforin. The functions of killer cells are tightly regulated through mechanisms like inhibitory receptor signaling and cytokine production, especially interferon gamma, to ensure targeted killing of harmful cells.

1. KILLER CELLS
Prepared by: Halala Dlzar Dhahir
Supervised by: DR. Amanj saeed

2. INTRODUCTION:
A type of immune cell that can kill tumor cells
or cells infected with a virus.
There are two major types of killer cells:
 Natural killer cells.
 T killer cells (cytotoxic killer cells)

3. NATURAL KILLER CELLS:
 Natural killer (NK) cells are effector
lymphocytes of the innate immune system
that control several types of tumors and
microbial infections by limiting their spread
and subsequent tissue damage.

4.  NK cells were originally described as large
granular lymphocytes with natural cytotoxicity
against tumor cells.
 NK cells were later recognized as a separate
lymphocyte lineage, with both cytotoxicity
and cytokine-producing effector functions.

5. NATURAL KILLER CELL TARGET
RECOGNITION:
 Natural killer (NK) cells target and kill aberrant cells, such
as virally infected and tumorigenic cells.
 NK cells can recognize and kill cells that have down-
regulated MHC class I molecules from their cell surface.
 The MHC class I molecules are recognized by NK cell
inhibitory receptors and the ligation of these receptors
inhibits the activation of NK cells.
 Conversely the lack of engagement of these receptors
can activate NK cytotoxicity

6.  Target cell recognition induces the formation of a lytic
immunological synapse between the NK cell and its
target.
 The polarized exocytosis of secretory lysosomes is then
activated and these organelles release their cytotoxic
contents at the lytic synapse, specifically for killing the
target cell.
 The essential role that secretory lysosome exocytosis
plays in the cytotoxic function of NK cells is highlighted by
immune disorders that are caused by the mutation of
critical components of the exocytic machinery.

7. T KILLER CELLS:
 Natural killer T (NKT) cells are lymphocytes
that express both a T-cell receptor (TCR),
characteristic of adaptive immunity, and
surface receptors for NK cells, which are
part of the innate immune response.
 These cells influence diverse immune
responses, including the surveillance for
tumors, the maintenance of self-tolerance
and the regulation of autoimmune diseases.

8. STRUCTURE OF T KILLER CELLS:
 T-cells have many identical T-cell receptors
that cover their surfaces and can only bind to
one shape of antigen.
 When a T-cell receptor fits with its viral
antigen on an infected cell, the Killer T-cell
releases cytotoxins to kill that cell.

9. FUNCTION OF CYTOTOXIC KILLER CELLS:
 T cells are generated in the Thymus and are programmed
to be specific for one particular foreign particle (antigen).
 Once they leave the thymus, they circulate throughout
the body until they recognize their antigen on the surface
of antigen presenting cells (APCs). The T cell receptor
(TCR) on both CD4+ helper T cells and CD8+ cytotoxic t
cell.
 cytotoxic T cells binds to the antigen as it is held in a
structure called the MHC complex, on the surface of the
APC.

10.  In order for the TCR to bind to the class I MHC molecule, the
former must be accompanied by a glycoprotein called CD8, which
binds to the constant portion of the class I MHC molecule.
Therefore, these T cells are called CD8+ T cells.
 This triggers initial activation of the T cells.
 The CD4 and CD8 molecules then bind to the MHC molecule
too, stabilizing the whole structure.
 This initial binding between a T cell specific for one antigen and
the antigen-MHC it matches sets the whole response in motion.
 This normally takes place in the secondary lymphoid organs.

12. PULLING THE TRIGGER: SECRETORY LYSOSOME
EXOCYTOSIS:
 Secretory lysosomes are dual function organelles that
combine the degradative function of conventional
lysosomes with the capacity to undergo regulated
exocytosis.
 The major cytotoxic proteins contained within
secretory lysosomes in NK cells and CTLs are the
granzymes and perforin.
 Target cell recognition induces secretory lysosome
exocytosis and the release of the cytotoxic contents
of this organelle.

13.  Perforin then facilitates the entry of the
granzymes into the target cell cytoplasm,
where they cleave a variety of targets, such
as caspases, resulting in cell death.

14. To ensure that NK cells do not kill indiscriminately, the exocytosis of secretory
lysosomes is a tightly regulated and highly ordered process.
For the purposes of this review it can be divided into four stages:
1. an activating, lytic immunological synapse forms at the point of contact with the
target cell, and there is a rearrangement of the actin cytoskeleton.
2. the microtubule-organizing centre (MTOC) of the NK cell and the secretory
lysosomes are polarized towards the lytic synapse.
3. secretory lysosomes dock with the plasma membrane at the lytic synapse.
4. fusing with the plasma membrane and releasing their cytotoxic contents.

15. REGULATION OF KILLER CELLS BY INTERFERON:
 IFN-γ production is important when considering
potential mechanisms of metabolic regulation of
this critical cytokine in NK cells.
 Regulation of IFN-γ production in NK cells
shares many aspects with T cells, including the
signaling pathways and transcription factors
(TFs) required for efficient transcription.

16.  However, a crucial difference between NK and T cells
is that mature NK cells have an epigenetically
accessible Ifng locus and constitutively express IFN-γ
transcript, whereas T cells do not.
 Acute transcription of Ifng requires nuclear factor
kappa light-chain enhancer of activated B cells (NF-
κB) activation, which is induced by the activating
receptors NKR or T-cell receptor (TCR) and/or the
cytokines interleukin-1 (IL-1) or IL-18

17. IFN-γ protein expression is regulated at
multiple levels, including epigenetically,
transcriptionally, and post-transcriptionally.

18. killer cells can be activated by three complementary and
often overlapping routes:
1. engagement of germline-encoded activating NKRs that
recognize stress- and virally induced ligands on target
cells in the absence of a strong inhibitory NKR signal.
2. recognition of antibody-coated target cells through the
activating Fc receptor CD16 (antibody-dependent
cellular cytotoxicity).
3. activation by innate and adaptive immune cytokines
including IL-1, IL-2, IL-12, IL-15, and IL-18.