1. Age-dependent changes in the
human T-cell repertoire
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3. Introduction:
The human immune system deteriorates with age in a
process termed Immunosenescence, significantly impacting
health and overall survival. The risk of death from infection
increases dramatically by age 65, the efficacy of vaccination
drops, and the increased rate of cancer seen in the elderly
has been associated with loss of immune function.

4. T cells constitute one of the two branches of the
adaptive immune system and are primary part of the
defense against intercellular parasites, including viral
infection. Once a virus infects a cell, the viral particle is
no longer visible to antibodies or to many of the human
innate defenses. The immune system has a special
mechanism to defend against these invading
pathogens. A fraction of every protein produced in a
cell is cut up and displayed on the surface of the cell,
thereby allowing the immune system to track the
internal environment of a cell. T cells bind these
presented peptides (pieces of a protein) and attack
cells that present foreign peptides.

5. Another type of T cell also plays a role in helping guide
other parts of the immune system. Newly developed T
cells, prior to expose to antigen, are called naive T cells,
and they are vital for creating a defense against new
pathogens or new strains of pathogens. These naive T
cells come in millions of different flavors, called
clonotypes, each clonotype expressing a unique T cell
receptor (TCR) on in its surface. The particular T cell
clonotype that binds to a pathogen derived peptide
expands rapidly and forms an immune response. The
large variety of naive clonotypes is vital to protect
against large number of number of new pathogens that
infect every human.

6. Immunological studies have uncovered significant age-
dependent changes in many parts of the immune system,
including adaptive immunity. Significant changes occur in the
signaling pathways of T and B cells, innate immunity with cell
dysfunction, and immune cell development with a reduction in
hematopoietic stem cell function and involution of the thymus.
Changes in the T cell repertoire have been suggested to play a
prominent role in age-related deterioration of the immune
system. The thymus, the site of T-cell maturation, begins to
involute at an early age, with a significant decrease in thymus
size and function during adolescence. This decrease in thymic
activity correlates with a significant decrease in naive T-cell
proliferation over time, with almost no new naive T cells
generated by age 60. Additionally, chemotherapy patients past
20 show very little ability to generate new naive T cells.

7. Despite reduction in production of new naive T cells with age,
the total number of T cells does not appear to significantly
decline until very old age. Proliferation of already developed T
cells is reported to make up for the lack of production of newly
rearranged T cells, with a homeostatic mechanism maintaining
the set population size. At present, a very limited number of
studies have attempted to evaluate the changes in the human T
cell repertoire with age. In addition, the methods utilized for
these studies are currently outdated and the conclusions drawn
relied on the extrapolation of results derived from a very small
sample set (a few dozen unique TCR sequences out of millions).
In these studies, a small set of randomly chosen T cells is likely to
be heavily biased towards the most common clonotypes.
Although studying a small number of TCRs can provide
information about the clone size of the largest clonotypes, it is
not possible to identify rare clones or, therefore, to evaluate the
true diversity of the T cell repertoire.

8. To address these issues of sample size and
clonotype frequency, my colleagues and I have
spent the last year developing a method to
deeply sequence 10ís of millions of TCR
sequences in parallel. In this project, we
propose to utilize this novel method to
determine the change in the repertoires of naive
and memory T cells with age. Additionally, we
propose to evaluate the efficacy of a potential
therapeutic, recombinant IL-7, to increase naive
T cell diversity.

9. normal

22. References:
-http://www.ellisonfoundation.org/content/age
repertoire-cell-t-human-changes-dependent
.fu7446/11/174http://www.jimmunol.org/content/
ll.pdf