The role of an asymmetric T lymphocyte division in generating diversity during adaptive immune responses

A hallmark of mammalian immunity is the heterogeneity of cell fate that exists among pathogen-experienced lymphocytes. Whether the diversity of T lymphocyte fates required for a productive immune response could emanate from the progeny of a single naïve T lymphocyte has not been resolved. To examine if the clonal descendants of a CD8+ T cell are heterogeneous or homogeneous, we have used adoptive transfer of pathogen-specific transgenic T cells in the context of infection in vivo. We now show that a dividing T lymphocyte initially responding to a microbe exhibits unequal partitioning of proteins that mediate signaling, cell fate specification, and asymmetric cell division. Asymmetric segregation of determinants appears to be coordinated by a prolonged interaction between the T cell and its antigen-presenting cell prior to division. Additionally, the first two daughter T cells displayed phenotypic and functional indicators of being differentially fated toward effector and memory lineages. We also have preliminary evidence suggesting memory CD8+ T lymphocytes exhibit properties of stem cells. Upon reencountering antigen, memory cells undergo asymmetric cell division achieving both terminal differentiation and self-renewal. These results reveal an unappreciated mechanism for mobile somatic cells to apportion diverse cell fates during division and provide for a plausible mechanism for a single lymphocyte undergoing clonal selection to achieve both terminal differentiation and self-renewal