The Cell Cycle Time of CD8+ T Cells Responding In Vivo Is Controlled by the Type of Antigenic Stimulus

Abstract

A hallmark of cells comprising the mammalian adaptive immune system is the requirement for these rare naïve T (and B) lymphocytes directed to a specific microorganism to undergo proliferative expansion upon first encounter with this antigen. In the case of naïve CD8+ T cells the ability of these rare quiescent lymphocytes to rapidly activate and expand into effector T cells in numbers sufficient to control viral and certain bacterial infections can be essential for survival. In this report we examined the activation, cell cycle time and initial proliferative response of naïve murine CD8+ T cells responding in vivo to Influenza and Vaccinia virus infection or vaccination with viral antigens. Remarkably, we observed that CD8+ T cells could divide and proliferate with an initial cell division time of as short as 2 hours. The initial cell cycle time of responding CD8+ T cells is not fixed but is controlled by the antigenic stimulus provided by the APC in vivo. Initial cell cycle time influences the rate of T cell expansion and the numbers of effector T cells subsequently accumulating at the site of infection. The T cell cycle time varies with duration of the G1 phase of the cell cycle. The duration of G1 is inversely correlated with the phosphorylation state of the retinoblastoma (Rb) protein in the responding T cells. The implication of these findings for the development of adaptive immune responses and the regulation of cell cycle in higher eukaryotic cells is discussed.

Systems-guided forward genetic screen reveals a critical role of the replication stress response protein ETAA1 in T cell clonal expansion

“…Interestingly, the only other cell type reported to proliferate at a rate comparable to effector T cells in vivo are dividing cells during mouse embryonic Table 2. GO/KEGG terms enriched in genes up-regulated within Etaa1 ΔEx2/ΔEx2 P14 cells development (3,36), and indeed the only other phenotype observed in Etaa1-deficient mice is partial embryonic lethality.…”

“…The simplest explanation is that ETAA1 becomes ratelimiting for ATR activation only in cells that proliferate exceptionally rapidly; in all other situations, Topbp1 can compensate for Etaa1 loss. Effector T cells proliferate in vivo at a much faster rate compared with T cells in vitro, and in fact have one of the fastest proliferation rates recorded (3). Interestingly, the only other cell type reported to proliferate at a rate comparable to effector T cells in vivo are dividing cells during mouse embryonic Table 2.…”

“…Failure of antigen-specific T cells to proliferate in response to replicating virus, bacterium, or yeast can lead to uncontrolled fatal infection. For this reason, T-cell proliferation in vivo in response to infection is one of fastest cell proliferation rates known (3). Fast cell division undoubtedly places enormous stress on proliferating T cells.…”

Manipulating DNA damage-response signaling for the treatment of immune-mediated diseases

“…In contrast to agents such as etoposide or cyclophosphamide, which damage DNA in essentially all cells (albeit more strongly in dividing ones) and throughout the cell cycle, PPCA relies on the unusual levels of DNA damage sustained by activated lymphocytes. Within the immune system, PPCA spares Tregs and nonactivated naive or memory T cells, likely because they are either not dividing or divide much more slowly (2,51). Thus, the high degree of susceptibility that activated lymphocytes display to PPCA, relative to other cell types, creates a favorable "therapeutic index," the ratio of potential therapeutic benefit to potential toxicity.…”

“…This mobilization is achieved by rapid, exponential expansion of responding lymphocyte clones. Indeed, antigen-activated T and B cells appear to have some of the most rapid division rates among all mammalian cell types (2). We hypothesized that this unique aspect of lymphocyte biology would cause significant genomic stress in responding lymphocytes and that novel forms of therapeutic immune suppression could be developed by exploiting this weakness.…”