Immunology

1. Natural Killer Cells
• A population of lymphocytes also responsible
for the mechanisms of innate immunity
• Recognizes components associated with
pathogens, damage, or stress and generates
rapid protective responses.
• a third branch of lymphoid cells (along with B
and T lymphocytes of the adaptive immune
system)
– All differentiate from the common lymphoid
progenitor into three separate lineages

2. • Express a limited set of invariant, non rearranging receptors
– These receptors enable the cells to be activated by indicators of
infection, cancer, or damage that are expressed by other cells
(In case of B and T lymphocytes, receptors have tremendous
diversity for foreign antigens)
• Are preprogrammed to respond immediately to appropriate
stimuli,
– release effector proteins from preformed secretory granules that
kill altered cells by inducing apoptosis
(However B and T cells require days of activation, proliferation,
and differentiation to generate their protective antibody and
cell-mediated immune responses.)
• This mechanism of cell-mediated cytotoxicity is also carried
out by cytotoxic T cells, which appear days later.

3. • NK cell-mediated cytotoxic activity is enhanced by IFN-α
produced early during virus infections.
• Activated NK cells also secrete cytokines—
– the proinflammatory cytokines IL-6 and TNF-α, as well as
– Type I IFNs and the Type II IFN, IFN-γ, a potent macrophage
activator that also helps to activate and shape the adaptive
response.
• Thus NK cells are an important part of the early innate
response to viral infections (as well as to malignancy and
other indicators of danger).
• These early innate responses control the infection for
the days to week it takes for the adaptive response
(antibodies and cytotoxic T cells) to be generated.

4. How do NK cells sense that our cells have become infected,
malignant, or potentially harmful in other ways?
• NK cells express a variety of novel receptors (collectively
called NK receptors).
• Members of one group serve as activating receptors
– activating receptors have specificity for various cell surface
ligands that serve as indicators of infection, cancer, or stress.
• NK cells also express TLRs, and binding of PAMPs or DAMPs
can add to the activation signals.
• To limit potential killing of normal cells in our body, NK cells
also express inhibitory receptors
– inhibitory receptors recognize membrane proteins (usually
conventional MHC proteins) on normal healthy cells and inhibit
NK-cell mediated cytotoxic killing of those cells.

5. • Many virus-infected or tumor cells lose expression of their
MHC proteins and thus do not send these inhibitory signals.
• Receiving an excess of activating signals compared to
inhibitory signals tells an NK cell that a target cell is
abnormal, and the NK cell is activated to kill the target cell.
• Thus NK cells are part of our innate sensing mechanisms that
provide immediate protection, in this case recognizing and
eliminating our own body’s cells that have become harmful.
• Initial activation increases the population and/or activity of
responding NK cells, which therefore would generate a
greater response when exposed later to the same activating
ligand(s).
– This resembles the immunological memory in the adaptive
immune system and represents the best example of
immunological memory in the vertebrate innate immune system.

6. Pathogens Have Evolved Mechanisms to Evade
Innate and Inflammatory Responses
• Most bacteria, viruses, and fungi replicate at high
rates and, through mutation, may alter their
components to avoid recognition or elimination by
innate immune effector mechanisms.
• Other pathogens have evolved complex
mechanisms that block normally effective innate
clearance mechanisms.
• A strategy employed especially by viruses is to
acquire genes from their hosts that have evolved
and function as inhibitors of innate and
inflammatory responses.

7. Interactions Between the Innate and Adaptive Immune Systems
• many layers of innate immunity are important to our health
• innate immunity is not sufficient to protect us fully from infectious diseases,
in part because many pathogens have features that allow them to evade
innate immune responses
• Hence the antigen-specific responses generated by our powerful adaptive
immune system are usually needed to resolve infections successfully.
• While our B and T lymphocytes are the key producers of adaptive response
effector mechanisms— antibodies and cell-mediated immunity— our innate
immune system plays important roles in helping to initiate and regulate
adaptive immune responses so that they will be optimally effective.
• In addition, the adaptive immune system has co-opted several mechanisms
by which the innate immune system eliminates pathogens, modifying them
to enable antibodies to clear pathogens.

8. The Innate Immune System Activates and Regulates Adaptive
Immune Responses
• When pathogens invade our body, usually by penetrating our
epithelial barriers,
– the innate immune system reacts quickly to begin to clear the invaders
– also plays key roles in activating adaptive immune responses.
• Innate cells at the infection site (resident macrophages, dendritic
cells, mast cells, and newly recruited neutrophils)
– sense the invading pathogens through their pattern recognition
receptors and
– generate antimicrobial and proinflammatory responses that slow down
the infection,
– also initiate steps to bring the pathogens to the attention of lymphocytes
and
– help activate responses that, days later, generate the strong antigen-
specific antibody and cell-mediated responses that resolve the infection.

9. • The first step in the generation of adaptive
immune responses to pathogens is the delivery of
the pathogen to lymphoid tissues where T and B
cells can recognize it and respond.
• Dendritic cells (usually immature) that serve as
sentinels in epithelial tissues bind microbes
through various pattern-recognition receptors and
carry the bound microbes— either still attached to
the cell surface or in phagosomes—via the
lymphatic vessels to nearby secondary lymphoid
tissues, such as the draining lymph nodes.
• There the dendritic cells can transfer or present
the microbes or microbial components to other
cells.

10. • In many cases the dendritic cell has internalized and
degraded the microbe, and microbe-derived peptides
come to the cell surface bound to its MHC class II
proteins.
• The binding of microbial PAMPs to the dendritic cell’s
PRRs also activates the dendritic cell to mature.
– It now expresses higher levels of MHC class II proteins and
– has turned on expression of costimulatory membrane
proteins, such as CD80 or CD86, that are recognized by
receptors on TH cells.
• As a result of these processes of microbe binding,
processing, and maturation, mature dendritic cells are
the most effective antigen-presenting cells, particularly
for the activation of naïve (not previously activated) TH
cells.