Homeostatic Turnover of Virus-Specific Memory CD8 T Cells Occurs Stochastically and Is Independent of CD4 T Cell Help

Abstract

Memory CD8 T cells persist by Ag-independent homeostatic proliferation. To examine the dynamics of this cell turnover, we transferred lymphocytic choriomeningitis virus specific memory CD8 T cells into naive mice and analyzed their in vivo division kinetics longitudinally in individual recipients.Using mathematical modeling, we determined that proliferation of this stably maintained memory CD8 T cell population was homogeneous and stochastic with a small fraction of cells completing division at any given time with an intermitotic interval of 50 d. This homeostatic turnover was comparable between memory CD8 T cells of different viral epitope specificities and also the total memory phenotype (CD44high) CD8 T cells. It is well established that CD4 T cell help is critical for maintenance of CD8 T cells during chronic infections, but recent studies have suggested that CD4 T cell help is also required for maintenance of memory CD8 T cells following acute infections. Hence, we assessed the role of CD4 T cells in Ag-independent maintenance of memory CD8 T cells. Consistent with previous reports, we found that memory CD8 T cells declined when transferred into MHC class II-deficient mice. However, their numbers were maintained stably when transferred into CD4 T cell-deficient mice. Interestingly, their homeostatic proliferation, ability to make recall responses, and phenotype were independent of CD4 T cell help because none of these qualities were affected when memory CD8 T cells were transferred and maintained in either MHC class II- or CD4-deficient recipients.

An Ag-Dependent Approach Based on Adaptive Mechanisms for Investigating the Regulation of the Memory B Cell Reservoir

“…Choo et al, in a recent paper published in The Journal of Immunology [57], reported the same finding, based on the Ag-independent premise. Choo et al (2010) have determined, by means of a quantitative analysis, that the homeostatic turnover of Agspecific CD8 memory T cells is stochastic rather than deterministic.…”

“…In 2009, Tarlinton et al [49] published a review paper, suggesting that the homeostasis of immune memory can only occur if new memory populations arise over others, i.e., to create dynamic equilibrium among memory cells, some need to disappear for others to arise, because the immune system has a maximum memory capacity [40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55]. Choo et al, in a recent paper published in The Journal of Immunology [57], reported the same finding, based on the Ag-independent premise. Choo et al (2010) have determined, by means of a quantitative analysis, that the homeostatic turnover of Agspecific CD8 memory T cells is stochastic rather than deterministic.…”

The lifestyle of memory CD8+ T cells

“…Indeed, we could demonstrate that BrdU can induce proliferation of memory T cells when given orally at a dose of 1 mg per ml in drinking water 10 . Based on our analysis of proliferation using cell cycle ana lysis and Ki67 staining, we feel it is fair to state that the extent of homeostatic proliferation has been largely overestimated previously [3][4][5][6] . We would not be too surprised if it turns out that homeo static proliferation does not have any role at all in the maintenance of memory CD4 + and CD8 + T cells.…”

“…Of mouse memory CD8 + T cells, more than 99% of the cells were in G0 or G1, according to PI staining, with 95% of them being in G0 according to Ki67 staining 10,16 . Both approaches are non invasive and do not involve the manip ulation of cells in vivo, unlike approaches based on bromodeoxy uridine (BrdU) or car boxyfluorescein succinimidyl ester (CFSE) labelling [3][4][5][6] . Indeed, we could demonstrate that BrdU can induce proliferation of memory T cells when given orally at a dose of 1 mg per ml in drinking water 10 .…”

“…Their numbers are deter mined by a balance between (homeostatic) pro liferation and cell death. It has been proposed that this proliferation mainly takes place in the bone marrow and is driven by interleukin 15 (IL 15), with an estimated turnover of the entire population within 2 months [3][4][5][6] . Memory CD8 + T cells from the bone marrow are thus considered to be part of the circulating memory T cell population.…”