Lymphocyte dynamics in health and disease

Abstract

Following immune depletion, it is vital that the immune system recovers rapidly to avoid severe or life-threatening infections. In adults, full recovery of CD4+ and CD8+ T-cell counts, important cell types of the immune system, may take years. Similar to other lymphocytes, T cells start their development in the bone marrow, but accomplish full maturation in the thymus. When mature T cells exit the thymus, they are antigen-inexperienced and are called 'naive'. Beside thymic naive T-cell generation, proliferation of naive T cells in the periphery is a source of naive T-cell production. The role of both mechanisms in the build-up of the naive T-cell compartment during childhood is not completely understood. In addition, the contribution of both mechanisms to naive T-cell recovery following immune deficiency is unclear. In this thesis, the establishment of the naive T-cell compartment during childhood was thoroughly assessed. Furthermore, the role of the thymus and peripheral proliferation during recovery of the T-cell compartment was determined: 1) in children who were treated with chemotherapy, 2) in children and adults who were treated with antiretroviral therapy for chronic HIV-1 infection, and 3) in children of whom the thymus had been completely removed in the first weeks of life. It was found that the thymus and peripheral proliferation both account for the establishment of the naive T-cell compartment during childhood. However, production of naive T cells by the thymus was crucial since only recently produced naive T cells by the thymus divide in the periphery. Thymic production was also important for the speed of naive T-cell recovery in children after cessation of chemotherapy. Peripheral proliferation may have contributed to naive T-cell recovery, but was not found elevated. This finding excludes the possibility that naive T-cell recovery is homeostatically regulated. Similar findings were observed in children for T-cell recovery during antiretroviral treatment for HIV-1 infection. Adults were also able to recover T-cell counts, but this took substantially longer (at least seven years of successful treatment) than in children (within one year). Beside these studies on T-cell dynamics in health and disease, a new method was created to identify naive T cells which have recently left the thymus, since these cells still bear thymic developmental features. By applying this method, the difficulty was resolved of discriminating between naive T cells that have recently been produced by the thymus and those that have circulated for years in the periphery. Collectively, the data presented in this thesis shed a new light on the mechanism of naive T-cell generation in health and disease. Therefore, in concert with the new method that was developed to identify recently produced naive T cells, physicians now have the opportunity to devise strategies that ameliorate naive T-cell recovery following immune depletion.