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MACROPHAGES AND KILLER T CELLS ROLE IN INNATE

IMMUNITY.

Introduction:
In this paper Macrophages and killer Tcells will be discussed, to show
their roles in the innate immunity.
The immune system consists of innate and adaptive immunity. The
innate immune system is the unlearned birth obtained physiological
protection against exposure of invading pathogenic molecules,
providing an immediate response capable of destroying invading cells.
However unlike adaptive immunity, where specific memory recognition
occurs, the innate immune response treats all foreign substances in
the same manner, with very limited number of antigens that can be
recognized on foreign cells. Although the presence of antigens are
greatly dispersed throughout cells, innate immunity lacks memory and
does not provide a source of lasting protection against future infection
by the same pathogen. (P.Delves 2008)

Natural Killer cells are part of the innate immune system playing a key
role in recognising and combating tumour, stressed cells and virally
infected cells.
They are large granular lymphocytes capable of killing their target cells
by causing them to go under apoptosis by releasing proteins from their
cytoplasm such as perforin and proteases. These proteins are called
granzymes. Recognition of Pathogenic molecule occurs by stimulation
of lectin-like receptors on the NK cell surface which bring Nk cells to
target opposition. (I.Roitt 1997).
Regulation of natural killer cells is very crucial to prevent it from
damaging the host cells rather than just the pathogenic cells. There
are different ways of activating NK cells by recognition of its target
cells; cytokine, antibody-dependent cellular cytotoxicity, active and
inhibitory receptors. (I.Roitt 1997).

NK cells use a duel receptor system, which determines if a human cell

should be killed or not. When cells are infected or stressed and are
turning into tumors, it triggers the production of molecules MICA and
MICB which then become placed on the surface of that specific cell.
Killer-activating receptors can now bind to these molecules, sending a
positive signal, if the positive signal is not canceled by a secondary
receptor known as killer-inhibitory receptor, the signal will then
activate the NK cell to attack and destroy the bounded cell. (E. Kaiser
2007)

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The killer-inhibitory receptor works by recognition of MHC-1 peptide

complex which sends a negative signal to override the positive kill
signal. MHC-1 molecules are located on all nucleated human cells, If
the MHC-1 molecules contain proteins from self bound to them, ones
that the CLT’s do not see as foreign, the cell would not be killed. When
proteins bound to MHC-1 molecules contain pathogenic peptides from
bacteria, viral or mutant it will trigger a kill signal.
When Nk cells are activated, it releases pore forming proteins known
as perforins, proteolytic enzymes and chemokines, which cleaves the
cell membrane of the target cells creating a transmembrane pore
channel. Granzyme B and other potential inducers of apoptosis can
now enter into the target cell, leading to the destruction of the cell by
the breakdown of cytoskeleton proteins and chromosomal degradation,
this breakdown results in broken cell fragments which are then be
subsequently removed by phagocytes. (E. Kaiser 2007)

Another form in which Natural killer cells link with phagocytes is

through Cytokines, these include interleukin-2, and interferon-gamma.
Once the Nk Cells have been activated a production of interleukin 2
and interferon gamma occur by the activation of Th1 lymphocytes
inside the NK cell, This activation as an effect causes large quantities
of Interferon-gamma to be produced, activating and attracting
macrophages to target and phagocytose target molecules. (E. Kaiser
2007)

Macrophages:
Macrophages are part of the Innate Immune System as they recognise
the pathogen, which leads to phagocytosis of the pathogen and the
secretion of it. A Macrophage is a phagocyte capable of phagocytosing
harmful particles which are seen as foreign, promoting an immune
response. Phagocytes are divided into two classes, professional and
non professional. Non-professional phagocytes lack phagocytic
receptors, where as professional phagocytes have phagocytic
receptors which are capable of detection of harmful objects (Roitt
1997).

Macrophages are a development from monocytes. This development

occurs after the monocytes has traveled through the blood to the
region of infection. Development of macrophages takes roughly 8
hours. During this period enlargement of monocytes cells occurs with
development of granules within itself (Delves 2008). The granules are
then packed with enzymes which assist in the digestion and killing of
foreign pathogen cells. Once formation of a macrophage has occurred,
they remain within the tissues affected where they phagocytose
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foreign cells, cell fragments, damaged and dead cells. Macrophages

secrete substances which attract other macrophages to the site of
infection and assist in T-cell pathogen recognition (P.Delves 2008).
Macrophages also act by releasing antimicrobial substances such as
lysozyme and lactoferrin which are capable of killing microbial
organisms (Stack 2010).

A case study performed by the University of Washington discusses the

effectiveness of the innate immune system, in recognizing pathogenic
patters by toll-like receptors found in macrophages.
Macrophages initiate an innate immune response firstly by recognising
the pathogen, phagocytosing then secreting.
Effectiveness of the macrophage innate response relies on recognition
of the pathogenic molecular patterns, which distinguishes the
pathogen from self and other microbial organisms. Recognition occurs
by the stimulation of toll-like receptors (TLR) located on the
macrophage, this case study was performed using
immunofluorescence microscopy on sheep and mice red blood cells
with tagged macrophages (V5 tagged TLR 6, HA-tagged TLR1 or TLR2)
tested against a variety of bacteria culture collection. (Streptococcus
pneumoniae, Enterococcus, Listeria monocytogenes, Lactobacillus, Staphylococcus aureus,
Escherichia coli) (Ozinsky at el 2000)

Results showed the effectiveness in TLR recognition, TLR2 has a broad

spectrum and recognizes gram positive bacteria, fungal and
mycobacterium .both TLR2 and TLR6 recognizes gram positive bacteria
by recognition of peptidoglycan. TLR4 recognizes gram negative
products lipopolysaccharides. Results showed that these three TLR’s can
activate the tumor necrosis factor drawing similarity to NK cell
function.
Effectiveness of TLR recognition is due to its structure. Each TLR is
composed of a type 1 protein membrane, containing a leucine-rich
domain (participates in ligand recognition), and a intracellular tail
consisting of conserved region (tollyIL-1R homology), when activated
results in production of MyD88 protein. MyD88 consists of a carboxyl-
terminal capable of interaction with various TLR’s. The MyD88 recruits
serine kinase which propagates the pro-inflammatory signal resulting

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in an inflammatory response, allowing for more macrophages to be

rushed to the infected region. (Ozinsky at el 2000)
Similarities in results can be seen by Kansas state university were
studies performed showed that TLR4 positive macrophages cleared
mice of Pasteurella pneumotropica-induced pneumonia, showing
TLR4’s effectiveness in bacterial clearance. ( Hart ML at el 2003)

In conclusion function of the innate immune system can be seen to

have great reliance in pathogen recognition, before the body triggers
such immune response identification from self and other is essential to
minimize harm, this was observed in the NK-cells duel receptor system
and with macrophages toll-like receptors.

REFERENCE:

P.Delves. (2008). Innate Immunity. Available:

http://www.merck.com/mmhe/sec16/ch183/ch183b.html. Last accessed 16 Sep 2010.

A.Ozinsky at el. (6/10/2000). The repertoire for pattern recognition of pathogens.

Available: http://www.pnas.org/content/97/25/13766.full Last accessed 16 sep
2010

I.Roitt (1997). ESSENTIAL IMMUNOLOGY. 9th ed. London: Blackwell, pg 18-20,33,316

Gary E. Kaiser. (2007). NATURAL KILLER (NK) CELLS . Available:

http://student.ccbcmd.edu/courses/bio141/lecguide/unit4/innate/nkcell.html. Last
accessed 16 sep 2010.

Collin Stack (2010). The Immune system, Innate immunity. Sydney: Uws Lecture
notes. p1-12.

Hart ML, Mosier DA, Chapes SK.. (2003). Toll-like receptor 4-positive macrophages
protect mice from Pasteurella pneumotropica-induced pneumonia. Infect immun. 1
(-), 663-70.