Grant: Operating Grant

White blood cells known as T lymphocytes, or T cells, are essential components of the immune system. They can be divided into two major groups: CD4+ T cells, which act as helper cells, directing the activity of other immune cells, and CD8+ T cells, which kill infected cells and tumor cells. The function of the thymus, the organ where T cells differentiate in order to perform specific functions, declines with age. When T cells become depleted in adults, they can undergo spontaneous, or homeostatic, proliferation in an attempt to restore their numbers. Although homeostatic proliferation efficiently regenerates CD8+ T cells, it is much less efficient in regenerating CD4+ T cells. For example, after high dose chemotherapy or stem cell transplantation, patients recover essentially each type of white blood cells within six to eight months except for CD4+ T cells that remain below normal levels for several years. As a result, lymphopenic patients are vulnerable to common and opportunistic infections, tumor recurrence and second malignant neoplasms. Dendritic cells are a specialized type of white blood cells that are important for naïve CD4+ T cell maintenance. We recently identified a regulatory circuit interfering with the capacity of dendritic cells to support naïve CD4+ proliferation. This grant will provide critical information about how lymphopenia (low T lymphocyte counts) affects dendritic cells and prevents CD4 regeneration. Furthermore, we will investigate how disruption of this regulatory circuit translates into safe and rapid CD4 regeneration. Finally, we will also investigate the recovery of other cell subsets (CD4+CD25+ T cells) important for the regulation of the immune system during lymphopenia.