Age-dependent changes in the human T-cell repertoire

2009 new Scholar Award in aging

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.

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. 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.

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.

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.

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.

Researchers
Harlan Robins PhD
Fred Hutchinson Cancer Research Center