Patrick Carey

HW1

2a) The PAMPs associated with gram-positive bacteria are its cell wall lipids,
Lipoteichoic acid, and the flagellin of the bacterium. TLR2 binds to bacterial
peptidoglycan, and TLR5 binds to bacterial flagellin. And TLR 1, 2 and 6 bind to
bacterial lipopeptides. All these TLRs are used in the innate immune recognition of
bacterial infection.
b) NK cells are activated by the cytokines IL-12 and IL-15, which are produced by
macrophages. NK cells produce IFN-, which then activates macrophages and
promotes the killing of phagocytosed bacteria. Via IL-12, IL-15, and IFN- the NK
cells and macrophages communicate and can determine whether to increase the
immune response in innate immunity.
c) Circulating antibodies do not confer the memory of the previous infection to T
and B cells. The antibodies in the serum can bind to the bacteria to communicate
the bacterias degradation to macrophage, but only until the antibodies themselves
are degraded. Thus the serum only provides a short-term response until its fully
degraded by the host. Thus the only way to transfer long term immunity is the
transfer of the memory cells/lymphoid cells to the new mouse, which can then
produce these antibodies and keep producing them until the bacteria has been
eradicated
For Effector T cells to be created that will recognize this antigen, first requires
presentation by Dendritic cells of the antigen to nave T cells along with costimulators. Effector T cells are activated by macrophages acting as the APC. If the
macrophages are activated, but have no effector T cell to activate, they will kill the
bacteria themselves until Nave T cells can gain memory of the antigen and become
effector T cells. By only transferring serum, none of the effector T cells are
transferred.
d) If a bacteria has the ability to escape through a phagosomes membrane, it can
escape degradation and thus also presentation of its peptide sequence to CD4+ T
cells (MHC-2 pathway). Once in the cytosol the bacteria can be degraded via the
MHC-1 pathway. Where the bacteria is digested by a proteasome, then the peptides
bind to the MHC-1 complex during biosynthesis, which then can activate CD8+ cells.

4a) For viral detection, TLRs can bind to viral nucleic acids. RIG-like receptors can
bind to viral RNA, and Cytsolic DNA sensors can bind to viral DNA. The general
molecule all these receptors bind to is nucleic acids, whether that is DNA or RNA
varies.
b) By avoiding the MCH-1 pathway, the virus avoids activation of CD8+ T cells. NK
cells have evolved to have a feedback loop with macrophages and not T cells(IL-1,

IL-2, IFN-), because then the innate immunity is independent of the adaptive
immunity and can still identify infected cells, even if the adaptive immune response
has been evaded.
c) Once the virus has infected a cell, it will inhibit class I MHC expression. However,
with this inhibition alters the inhibitory receptor present on the cell that would tell
NK cells that it is a healthy native cell. So by inhibiting the MHC-1 pathway, the
virus alters the cell such that NK cells will not activate and kill the cell.

5a) The epithelium barrier prevents entry of microbes by providing a physical

barrier to infection. The keratinocytes actively respond to microbes and produce
anti-microbial peptides, to kill the microbes, and produce cytokines to control the
immune response to the invading microbe. Inside the epithelial layers, there are
also effector CD8+ cells that can respond to invasion.
If a protozoa is too large to be phagocytosed, NK cells can still kill the cell. NK cells
can directly kill by binding to the protozoa and releasing granzymes (induce
apoptosis) or perforin (form pores in cell) into the foreign cell.
b) Th1 cells help macrophages by producing IFN-, which activates the transcription
factor STAT1 in macrophages and stimulates the expression of several enzymes in
macrophages that produce efficient killers of microbes (ROS, iNOs, NO). Th1 also
activates macrophages via the CD40/CD40L interaction.
c) To stimulate the differentiation of Th1 cells requires IFN- and IL-12. IFN- also
inhibits the formation of Th2 and Th17 cells. IFN- is also the major activator of
existing Th1 cells. A traditional vaccine does induce the formation and
differentiation of these memory Th1 cells, but a vaccine traditionally does not
contain IFN-, as IFN- induces formation of Th1 cells, which themselves produce
more IFN-, leading to almost a positive feedback loop, which can be dangerous.

6) By destroying all BM cells and BM derived cells via radiation, removes all B cells
from the body of the mouse and all potential to produce new B cells. Then supplying
bone marrow that is of a different MHC haplotype, means the mouse now has
essentially inherited the memory B cells of another haplotype, and now contains
essentially two haplotypes, significantly lowering its ability even further to fight
infection. Another possibility is by having mismatching B and T cell haplotypes, may
lead to an autoimmune reaction making the mouse not be able to fight infection
because its T and B cells are essentially combating one another.
By completely replacing the major T cell and B cell sources in mouse B with mouse
As thymii and bone marrow, means mouse B now expresses mostly just the H-2k
haplotype, instead of a mix of haplotypes. And perhaps the propensity to clear
bacterial infections and be especially susceptible to viral infections is how the H-2k
haplotype manifests itself.

7a) IFN- and IL-12 when both produced, initiate the differentiation of Th1 cells from
CD4+ T cells. They both also simulate the differentiation of nave CD8+ T cells to
CTLs.
b) First the antigen is uptaken by macrophages and dendritic cells in the innate
immune response. The antigen then triggers the dendritic cells and macrophages
to excrete IL-12, which triggers NK cells and T cells to produce IFN-. When IL-12 and
IFN- are both present they act as costimulators with the APC to initiate the
differentiation of CTLs and Th1 cells.

c) IFN- tells B cells to switch to IgG antibody creation

d) If IL-4 is produced instead, then B cells would switch to production of IgE
antibodies. CH4+ cells would differentiate to Th2 cells and Mast cells would
proliferate. The difference in response to IL-12/IFN- to IL-4 is that these cytokines
activate different pathways and are cofactors for different reactions that occur.
e) The IL-12/IFN- would be most effective in combating tumors. As these stimulate
the creation of CTLs from CD8+ cells which will directly kill the tumor cells. While IL4 activates CD4+ cells to produce antibody and through a roundabout method may
induce the creation of CTLs to combat the tumor, but not as quickly or directly if it
does.