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Vera van Hoeven

Tuesday 13 October 2015

Lymphocyte dynamics in healthy and lymphopenic conditions

Promotor: Prof. dr. F. Miedema
Defence: 13 October 2015

By a balance of cell production and cell loss, B-cell and T-cell populations are generally maintained at a relatively stable size throughout life. Following lymphocyte-depleting therapies however, for example for the treatment of hematological malignancies, reconstitution of some lymphocyte subsets typically takes months to years. Such long-term immunodeficiency results in an increased susceptibility to infectious and malignant diseases and is associated with an increased mortality.

Why recovery of these lymphocyte subsets takes so long is poorly understood. To be able to understand the process of immune reconstitution, and how for example advanced aging, and chronic infections affect the lymphocyte compartment, it is essential to first understand how lymphocyte populations are maintained in healthy conditions. The studies in this thesis were focused on investigation of B-cell and T-cell dynamics in healthy conditions and in conditions in which lymphocyte numbers are reduced. By performing in vivo stable isotope labeling studies in healthy volunteers and in lymphopenic stem-cell transplanted and kidney-transplanted patients, we studied how healthy aging, therapeutic lymphocyte depletion, and immunosuppressive therapy affect lymphocyte production and survival rates. In combination with T-cell receptor excision circle analyses and mathematical modeling, we also investigated the relative contributions of thymic output and peripheral cell division to maintenance of the naive T-cell population. The main findings of these studies are that (i) thymic output contributes very little to T-cell production from young adulthood onward, and declines approximately tenfold between the third and seventh decade of life, (ii) the turnover rate of B-cell and T-cell subsets is not substantially altered during healthy aging and despite declining thymic output and naive T-cell numbers with age, the level of peripheral naive T-cell division is not increased in elderly, (iii) in severely lymphocyte-depleted stem-cell transplanted individuals, the cell production rates of deficient B-cell and T-cell subsets are significantly increased, (iv) thymic output and peripheral cell division both contribute substantially to T-cell reconstitution, and (v) in kidney transplantation patients treated with immunosuppressive therapy, low lymphocyte counts do not result in increased cell production rates. These results suggest that in conditions of severe lymphopenia, a homeostatic response enhances the production rate of deficient lymphocyte subsets. At the same time, lymphocyte maintenance during healthy aging does not require substantial alterations in cellular turnover rates.

In addition to the human studies, we also performed thymus transplantation and stable-isotope labeling studies in mice to investigate the composition and dynamics of the naive T-cell population in more detail. Our findings suggest that T cells that have recently been produced by the thymus, the recent thymic emigrants, form a subpopulation with distinct kinetics, and are relatively short-lived cells in the naive T-cell pool.

Altogether, our fundamental insights into the dynamics of lymphocyte populations will aid the interpretation of past, current, and future investigations in a variety of interventions and diseases, and may form the basis for the development of improved therapeutic strategies that either limit the damage to the lymphocyte compartment, or accelerate immune reconstitution following lymphocyte depletion.