T Cell Effector Function and Anergy Avoidance Are Quantitatively Linked to Cell Division

Strong memory T cell responses result partly from the selection of Ag-specific clones during immunization. In this study, we show that a monoclonal CD8 T cell population expressing a unique TCR is heterogeneous in terms of clonogenic potential following activation under optimal conditions. More importantly, the frequency of clonogenic cells is strongly increased among Ag-experienced cells, indicating that these cells were either generated or selected during the in vivo primary response. Moreover, strong proliferative responses of primed cells result from this enhanced frequency, as proliferating naive and primed cells display the same cycling parameters, i.e., lag time and intermitotic interval. Hence, these results suggest that the clonogenic potential of individual cells is imprinted before Ag encounter and that clonogenic precursors are selected or generated following in vivo activation.

Section: Discussionsupporting

confidence: 67%

Hyperproliferative Response of a Monoclonal Memory CD8 T Cell Population Is Characterized by an Increased Frequency of Clonogenic Precursors

Arpin

Angelov

Walzer

et al. 2002

“…Interestingly, this effect was associated with maintained T cell responsiveness and reversal of T cell anergy and was not a consequence of simply increasing T cell numbers. This is consistent with the defined property of IL-7 and other common ␥-chain-binding cytokines to reverse T cell anergy in vitro (37,38). Our results suggest that lymphopeniainduced homeostatic proliferation is an effective method for preventing and reversing tumor-induced CD8 ϩ T cell anergy in vivo, representing a strategy that is attractive for clinical translation.…”

supporting

confidence: 70%

Homeostatic Proliferation as an Isolated Variable Reverses CD8+ T Cell Anergy and Promotes Tumor Rejection

Brown

Blank

Kline

et al. 2006

Although recent work has suggested that lymphopenia-induced homeostatic proliferation may improve T cell-mediated tumor rejection, there is little direct evidence isolating homeostatic proliferation as an experimental variable, and the mechanism by which improved antitumor immunity occurs via homeostatic proliferation is poorly understood. An adoptive transfer model was developed in which tumor-specific 2C/RAG2−/− TCR transgenic CD8+ T cells were introduced either into the lymphopenic environment of RAG2−/− mice or into P14/RAG2−/− mice containing an irrelevant CD8+ TCR transgenic population. RAG2−/−, but not P14/RAG2−/− recipients supported homeostatic proliferation of transferred T cells as well as tumor rejection. Despite absence of tumor rejection in P14/RAG2−/− recipients, 2C cells did become activated, as reflected by CFSE dilution and CD44 up-regulation. However, these cells showed poor IFN-γ and IL-2 production upon restimulation, consistent with T cell anergy and similar to the hyporesponsiveness induced by administration of soluble peptide Ag. To determine whether homeostatic proliferation could uncouple T cell anergy, anergic 2C cells were transferred into RAG−/− recipients, which resulted in vigorous homeostatic proliferation, recovery of IL-2 production, and acquisition of the ability to reject tumors. Taken together, our data suggest that a major mechanism by which homeostatic proliferation supports tumor rejection is by maintaining and/or re-establishing T cell responsiveness.

“…In naive mouse cells, Th1/Th2 cytokine expression is cell cycle-dependent, suggesting that the role of IL-2 is to drive such cells to cycle (61). By contrast, previously activated cells that have not undergone cell division can express CD25 and produce IFN-␥ upon restimulation to the same extent as cells that had divided earlier (62). We find in a bulk population of human PBMC that inhibiting IL-2R signaling blocks cytokine production prior to cell division and, at least for IFN-␥, this occurs both in presumably naive (CD45RA) and memory (CD45RO) cells.…”

Section: Discussionmentioning

confidence: 95%

IL-2 Receptor Blockade Inhibits Late, But Not Early, IFN-γ and CD40 Ligand Expression in Human T Cells: Disruption of Both IL-12-Dependent and -Independent Pathways of IFN-γ Production

McDyer

John

et al. 2002

mAbs directed against the α-chain (Tac/CD25) of the IL-2R are an emerging therapy in both transplantation and autoimmune disease. However, the mechanisms underlying their therapeutic efficacy have not been fully elucidated. Therefore, we examined the affect of IL-2R blockade on Th1 and Th2 cytokine production from human PBMC. Addition of a humanized anti-Tac Ab (HAT) to activated PBMC cultures inhibited IFN-γ production from CD4 and CD8 T cells by 80–90%. HAT partially inhibited production of TNF-α and completely inhibited production of IL-4, IL-5, and IL-10. Furthermore, IL-12, a central regulatory cytokine that induces IFN-γ, was undetectable in treated cultures. As T cell-dependent induction of IL-12 is regulated via CD40/CD40 ligand (CD40L) interactions, we examined the affect of HAT on CD40L expression. We found CD40L expression to be biphasic with an early (6 h) peak that is CD28/IL-2-independent, but a later peak (48 h) being CD28/IL-2-dependent and inhibited by HAT. Similarly, IFN-γ production at 6 h was CD28/IL-2-independent but CD28/IL-2-dependent and inhibited by HAT at 48 h. Nonetheless, addition of rCD40L or exogenous IL-12 to HAT-treated cultures could not restore IFN-γ production. The IFN-γ deficit in such cultures appears to be due to a direct inhibition by HAT of IL-12-independent IFN-γ production from T cells rather than altered expression of either the IL-12Rβ1 or IL-12Rβ2 chains. These data demonstrate that IL-2 plays a critical role in the regulation of Th1 and Th2 responses and impacts both IL-12-dependent and -independent IFN-γ production.