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Combine B cells and T cells?

Use foreign peptide in thymic education to prevent autoimmunity

-use plasmid to capture DNA to transcribe foreign peptide
-CRISPR/Cas-9?
-ribozymes?

Try to avoid pre-thymocyte death

KEY CONSIDERATIONS:
-diversity generation
-positive and negative selection to avoid AID
-innate vs. adaptive
-immune cell trafficking/secondary lymphoid organs as central sites of adaptive immunity
-immune memory
-mucosal immunity/tolerance
-cancer
-alloreactivity
-transplants, etc
The innate immune system will remain largely unchanged. This system currently works
quickly and effectively to recognize a broad array of pathogens and relay information to the
adaptive immune system. This includes the use of macrophages and mucosal immunity. We
have also decided to keep but redesign the thymic education in our system, as our innate
immune system cannot protect specifically and we need a precise and accurate way of fighting
pathogens.
One way for us to redesign and improve the human immune system to avoid
autoimmune disease would be to create a system that replaces self-peptide with foreign peptide
in positive selection of thymic education. Our system would have dendritic cells and other APCs
not only uptake and present foreign antigen, but also extract DNA sequences coding for said
antigen, home to the thymus, and transfer this foreign antigen DNA to thymic dendritic cells
specializing in collecting this foreign DNA... Thus, surviving T cells would be educated on a self-
MHC + foreign-peptide complex, avoiding the issue of affinity to self-MHC and self-peptide as
currently seen in the immune system and awkwardly dealt with during negative selection. This
would help us fight autoimmunity by avoiding the survival of T cells that recognize self antigen.
Essentially, the cells that pass positive selection would then move on to negative selection
where self peptide is expressed. If any cells in the negative selection process recognize the self
MHC with the self-peptide it would be selected against.
 We would make the antigen repertoire available by using a CRISPR/Cas-9 type of
system seen in many bacterial cells. Each educating thymic cell would have a plasmid that
codes for small bits of previously seen pathogen in the body. This system is used in bacterial
cells to confer antibacterial and antiviral resistance. Each cell in the thymus would have a large
portion of the genetic material of foreign RNA seen in the past and would express them each
randomly, yet equally, educating T cells on foreign antigen. They could be conferred from
mother to child through similar hereditary mechanisms as the mitochondrial DNA, and would
replicate similarly to the mechanisms seen with mitochondrial DNA so that offspring could start
off with a library of antigen to protect itself. Dendritic cells, in the thymus, would be the only cells
expressing this and during positive selection the cells would utilize a factor similar to AIRE to
express all the antigen information stored in the plasmid. These cells could spread the plasmid
DNA to each other through horizontal gene transfer. This would help with autoimmunity,
because the only T cells that are activated are T cells that react with foreign peptide during the
positive selection stage.

Human immunity, as we have learned throughout the course of the semester, is a

wondrously complex and powerful system, adapted and refined to protect and heal from myriad
mechanisms of attack. In this assignment, though, we play God to explore how we might
redesign aspects of the immune system to improve their functions. Since Mother Natures
approach has been to allow slow, stochastic developments to take their course, though, our
approach might be more aptly dubbed playing human.
The innate immune system does well to recognize and eliminate a broad array of basic
pathogens, so we would leave it mostly unchanged. However, we would redesign some of its
interactions with the adaptive response, such as in thymic education.
To prevent autoimmune disease, we would redesign positive selection in the cortex of
the thymus to educate thymocytes against self-MHC + foreign-peptide complex instead of
against both self MHC and peptide. This would circumvent the dilemma of requiring partial self-
peptide affinity for thymocyte survival. The removal of self peptide from positive selection, along
normal existing negative selection and anergy mechanisms, would likely stop all autoreactive T
cells at various stages their development.
To collect this foreign antigen repertoire, we would implement a CRISPR/Cas-9 system
allowing APCs to incorporate the coding DNA sequence of their uptaken antigen in a plasmid.
The APCs would home to the thymus and transfer this genetic material to the cTECs
responsible for positive selection. These cTECs would express a homologue of AIRE allowing
for random expression of these foreign antigen DNA sequences. Thus, the cTECs would have a
large portion of foreign genetic material coding for previously seen pathogenic antigen (only
transcribed in cTECs) and randomly express these antigens on their MHC molecules to educate
emerging thymocytes. (The foreign genetic repertoire could be conferred from mother to child
through similar hereditary mechanisms as seen in mitochondrial DNA so that offspring have an
initial library of foreign antigen for thymic education.) The benefits of this are threefold: T cells
with high affinity to foreign peptide in positive selection can now be kept, only T cells
recognizing foreign antigen are allowed to survive during positive selection, and any T cells also
binding self peptide, even with weak affinity, can be thoroughly eliminated during negative
selection. This should remove virtually all autoreactivity.
 We would also like to change the system of nucleotide addition and subtraction by TDT
in the pre-B and pre-T cells. Instead of randomly adding and subtracting nucleotides to create
diversity, only a multiple of three nucleotides will be added or subtracted. This is to lower the
chances of creating RNA that cant be successfully translated, without negatively influencing
diversity.
The lymph nodes, other secondary lymphoid organs, and trafficking mechanisms would
be preserved in their current form, since they provide effective circulation and matchmaking of
a diverse array of lymphocytes and their targets. However, to improve the speed of the adaptive
response, we would design a portion of the memory T cells after an immune response to home
to the tissue where its antigen was originally encountered. There, the antigen-specific T cells
would stay and act like intraepithelial lymphocytes, responding rapidly but specifically to their
antigen should it be encountered again.
We would redesign the human system to have oral tolerance in order to promote
mucosal tolerance and foster symbiotic microbiome growth. This can also be used as a method
to tolerize the body to transplants - the hosts body can be orally tolerized to the donors MHC
(and other key potential antigens) to prevent transplant rejection.
To alter the immune system for better protection and cytotoxicity against cancer, we will
modify apoptotic and other immunosuppressive signal receptors, with coreceptors for a series of
common tumor cell markers. If the coreceptor bound any sort of cancer cell marker, it would
inactivate the apoptotic/immunosuppressive pathway and instead induce effector cytokine
production to stimulate immune activity. This is a twofold solution. Since apoptotic and
immunosuppressive ligands are commonly expressed on cancer cells as a mechanism of
immune escape, this coreceptor signal would prevent tumor-induced immunity damage.
Moreover, since the coreceptor would instead stimulate cytotoxicity (as is currently induced in
medicine through checkpoint inhibitors), immune function against cancers would be greatly
enhanced.
As a final act of divine intervention, to mitigate the scourge of HIV/AIDS, we would
confer the delta 32 mutation of CCR5 and a similar mutation of CXCR4 upon the whole human
population.
(734 words)

an immune checkpoint often exploited by cancers as a mechanism of immune escape, to

require a costimulatory signal. The costimulatory molecule would be present on all normal
cells but absent, damaged, or modified on cancer cells to prevent cancerous immune
suppression. An example of a co-ligand of PD-L1 could be Class I MHC, since cancer cells
often downregulate Class I MHC as another attempt of immune escape. Since all healthy cells
express Class I MHC, the healthy regulatory effects of PD-1 to prevent autoimmunity will be
unaffected, but cancer cells will no longer be able to exploit its apoptotic pathways of killing
effector T cells. This is one of many possible