A Biochemical Signature for Rapid Recall of Memory CD4 T Cells

Abstract

Mechanisms for the rapid recall response mediated by memory T cells remain unknown. In this study, we present a novel, multiparameter analysis of TCR-coupled signaling and function in resting and activated naive and memory CD4 T cells, revealing a biochemical basis for immunological recall. We identify a striking elevation in expression of the proximal tyrosine kinase Zap70 in resting Ag-specific and polyclonal mouse memory vs naive CD4 T cells that is stably maintained independent of protein synthesis. Elevated Zap70 protein levels control effector function as IFN-γ production occurs exclusively from the Zap70high fraction of activated T cells in vitro and in vivo, and specific down-modulation of Zap70 expression in memory CD4 T cells by small interfering RNA or protein inhibition significantly reduces rapid IFN-γ production. Downstream of Zap70, we show quantitative differences in distal phosphorylation associated with effector function in naive and memory subsets, with low accumulation of phosphorylation in memory T cells producing IFN-γ at early time points, contrasting extensive phosphorylation associated with IFN-γ production following sustained activation of naive T cells. Our results reveal a novel biochemical signature imparted to memory CD4 T cells enabling efficacious responses through increased Zap70 expression and reduced accumulation of downstream signaling events.

Bystander stimulation of activated CD4+ T cells of unrelated specificity following a booster vaccination with tetanus toxoid

“…These are clearly not equivalent to the long-term memory cells specific for purified protein derivative and C. albicans, which existed in the human subjects. However, they are not unrelated to memory cells since such cells will spontaneously differentiate into memory cells on transfer into naive recipients [17][18][19][20][21].…”

“…IL-2 and IFN-g ELISPOT assays (see IL-2 and IFN-g ELISPOT section) were used to check efficacy of priming and boosting at week 2 and 6, respectively. After boosting, mice were left for at least 8 wk, a period of time long enough for T-cell memory to be established [17,18]. At the end of this period, levels of TT-specific T-cell responses were checked again and used as baseline reference for the final experiment.…”

IL-27 Receptor Signaling Regulates Memory CD4 + T Cell Populations and Suppresses Rapid Inflammatory Responses during Secondary Malaria Infection

“…Loss of cell-intrinsic WSX-1 expression by memory CD4 ϩ T cells and consequent loss of IL-27-mediated regulation may then lead to enhanced memory CD4 ϩ T cell reactivation, including increased IFN-␥ production and excessive inflammation. In this scenario, it is foreseeable that direct IL-27R signaling inhibits NF-Bp50 or Zap70 signaling, both of which are necessary for rapid IFN-␥ production by memory CD4 ϩ T cells (34,35). In the second scenario, loss of WSX-1 receptor expression within the innate system, rather than on memory CD4 ϩ T cells, drives the heightened anamnestic immune responses observed in WSX-1 Ϫ/Ϫ mice.…”

Human CD4+ effector T lymphocytes generated upon TCR engagement with self-peptides respond defectively to IL-7 in their transition to memory cells

“…1 T cells Biochemical differences between naive, effectors and memory CD4 1 T cells have been previously reported in mice [27][28][29][30][31][32] and humans, 33,34 such in the total protein tyrosine phosphorylation, in the expression of CD3f-associated kinase 70 (ZAP-70) and SH2-containing leukocyte molecule of 76 kDa (SLP-76), or in the activation of the mitogen-activated protein kinase Erk-1/2. Thus, we next analysed the biochemical profile of Tmem to evaluate whether they actually acquired memory-cell properties.…”