Marilyn Thoman, Ph.D., Associate Professor

Immunology Program

T CELL DEVELOPMENT AND MATURATION IN THE AGED: STRATEGIES FOR INTERVENTION

Laboratory Staff: Joy Phillips, Theresa Brondstetter, and Chauca English

Advancing age is accompanied by an increasing risk of infectious disease and cancer, thought to be in part due to alterations in protective immune function. Amongst the cells which comprise the immune system, the helper ( CD4+) T lymphocytes are particularly susceptible to age-related changes and display a marked shift in their subset composition with age. At least three functionally distinct subpopulations of CD4+ T cells can be distinguished. These populations are; antigen-inexperienced naive cells, activated effector cells, and memory cells. Each population can be identified by a unique profile of cell surface marker expression and pattern of cytokine production. In young individuals the relative distribution of these subsets favors a high percentage of naive T cells, with a much lower fraction of either effectors or memory cells. As the individual ages, this balance shifts, such that the predominate subset becomes the memory, or memory/effector. This change alters the type and amount of cytokines which are released upon contact with antigen, which in turn directs the subsequent cellular responses. The decline in the number of naive CD4+ cells suggests that the repertoire becomes restricted with age limiting the ability of the individual to respond to antigenic determinants newly encountered in later life.

Over the past two years our work has focused on regenerating a CD4+ T cell population in aged mice which more closely resembles that found in young animals, ie. enriched in naive cells. Our model system employs bone marrow transplantation following high dose irradiation. By means of this regimen peripheral T cells are depleted by greater that 90%, but over the course of 8 to 12 weeks regenerate to numbers approaching pre-treatment levels both by expansion of radioresistant host T cells , and new T cell differentiation from donor bone marrow-derived precursors. However, in contrast to our expectations, the T lymphocyte compartment in these aged mice was not enriched in naive cells. As in untreated control mice, the CD4+ population contained a majority of CD44hiCD45RBlo L-selectinlo cells which upon activation produce large amounts of gamma-IFN and IL-1 , characteristic of memory cells.

Investigations now focus on answering the question of why aged animals regenerate a memory-enriched population rather than a naive-enriched population . Mechanisms which have been investigated include: age-related changes in the differentiative environment of the thymus, or alterations within the peripheral environment of the aged animals which accelerate the maturation of the naive T cell to the memory state. While these studies are still in progress, our preliminary evidence suggests that it is the second of these two proposed mechanisms which is responsible. It is likely that activation through the T cell receptor complex plays a role in this process. It is anticipated that the results of these studies will suggest ways in which the recovery of immune function following irradiation and/or chemotherapy can be accelerated.

A second line of investigation in my laboratory concerns the process of T cell differentiation. The production of T lymphocytes occurs primarily in the thymus. However, the thymus undergoes with age a process known as involution, in which the structure of the organ becomes disorganized and the lymphoid portion is lost, significantly reducing the production and release of new T cells during adult life. This too contributes to the decline in the fraction of naive T cells in older individuals. We have sought to determine how advancing age affects T cell differentiation and have identified several transition points which are particularly age-sensitive. The aquisition of CD25 by the earliest T cell precursors is one step which shows reduced activity with aging. Another is the entry of cells into cycle which occurs at the DN to DP transition, which is also curtailed in the aging thymus. These steps are targets for intervention in the involution process which could result in the maintenance of vigorous T cell production into later life.

Our goal is to understand how aging alters the differentiation and function of cells of the immune system and identify means by which to prevent or reverse this process. Such interventions will be particularly valuable not only for the general population, but also in clinical situations where immune function is compromised, such as in patients with AIDS or following chemotherapy.