CD4 T-cell memory generation and maintenance.

Immunologic memory is the adaptive immune system's powerful ability to remember a previous antigen encounter and react with accelerated vigor upon antigen re-exposure. It provides durable protection against reinfection with pathogens and is the foundation for vaccine-induced immunity. Unlike the relatively restricted immunologic purview of memory B cells and CD8 T cells, the field of CD4 T-cell memory must account for multiple distinct lineages with diverse effector functions, the issue of lineage commitment and plasticity, and the variable distribution of memory cells within each lineage. Here, we discuss the evidence for lineage-specific CD4 T-cell memory and summarize the known factors contributing to memory-cell generation, plasticity, and long-term maintenance.

FoxO1 controls effector-to-memory transition and maintenance of functional CD8 T cell memory.

During a T cell response, naive CD8 T cells differentiate into effector cells. Subsequently, a subset of effector cells termed memory precursor effector cells further differentiates into functionally mature memory CD8 T cells. The transcriptional network underlying this carefully scripted process is not well understood. In this study, we report that the transcription factor FoxO1 plays an integral role in facilitating effector-to-memory transition and functional maturation of memory CD4 and CD8 T cells. We find that FoxO1 is not required for differentiation of effector cells, but in the absence of FoxO1, memory CD8 T cells displayed features of senescence and progressive attrition in polyfunctionality, which in turn led to impaired recall responses and poor protective immunity. These data suggest that FoxO1 is essential for maintenance of functional CD8 T cell memory and protective immunity. Under competing conditions in bone marrow chimeric mice, FoxO1 deficiency did not perturb clonal expansion or effector differentiation. Instead, FoxO1-deficient memory precursor effector cells failed to survive and form memory CD8 T cells. Mechanistically, FoxO1 deficiency perturbed the memory CD8 T cell transcriptome, characterized by pronounced alterations in the expression of genes that encode transcription factors (including Tcf7), effector molecules, cell cycle regulators, and proteins that regulate fatty acid, purine, and pyramidine metabolism and mitochondrial functions. We propose that FoxO1 is a key regulator that reprograms and steers the differentiation of effector cells to functionally competent memory cells. These findings have provided fundamental insights into the mechanisms that regulate the quality of CD8 T cell memory to intracellular pathogens.

p27(Kip1) negatively regulates the magnitude and persistence of CD4 T cell memory.

Much is known about the differentiation of naive T cells into distinct lineages of effector cells, but the molecular mechanisms underlying the generation and maintenance of CD4 T cell memory are poorly characterized. Our studies ascribe a novel role for the cell cycle regulator p27(Kip1) as a prominent negative regulator of the establishment and long-term maintenance of Th1 CD4 T cell memory. We demonstrate that p27(Kip1) might restrict the differentiation and survival of memory precursors by increasing the T-bet/Bcl-6 ratio in effector CD4 T cells. By promoting apoptosis and contraction of effector CD4 T cells by mechanisms that are at least in part T cell intrinsic, p27(Kip1) markedly limits the abundance of memory CD4 T cells. Furthermore, we causally link p27(Kip1)-dependent apoptosis to the decay of CD4 T cell memory, possibly by repressing the expression of γ-chain receptors and the downstream effector of the Wnt/ß-catenin signaling pathway, Tcf-1. We extend these findings by showing that the antagonistic effects of p27(Kip1) on CD4 T cell memory require its cyclin-dependent kinase-binding domain. Collectively, these findings provide key insights into the mechanisms underlying the governance of peripheral CD4 T cell homeostasis and identify p27(Kip1) as a target to enhance vaccine-induced CD4 T cell memory.

Signal integration by Akt regulates CD8 T cell effector and memory differentiation.

During a T cell response, the effector CTL pool contains two cellular subsets: short-lived effector cells (SLECs), a majority of which are destined for apoptosis, and the memory precursor effector cells, which differentiate into memory cells. Understanding the mechanisms that govern the differentiation of memory CD8 T cells is of fundamental importance in the development of effective CD8 T cell-based vaccines. The strength and nature of TCR signaling, along with signals delivered by cytokines like IL-2 and IL-12, influence differentiation of SLECs and memory precursor effector cells. A central question is, how are signals emanating from multiple receptors integrated and interpreted to define the fate of effector CTLs? Using genetic and pharmacological tools, we have identified Akt as a signal integrator that links distinct facets of CTL differentiation to the specific signaling pathways of FOXO, mTOR, and Wnt/ß-catenin. Sustained Akt activation triggered by convergent extracellular signals evokes a transcription program that enhances effector functions, drives differentiation of terminal effectors, and diminishes the CTLs' potential to survive and differentiate into memory cells. Whereas sustained Akt activation severely impaired CD8 T cell memory and protective immunity, in vivo inhibition of Akt rescued SLECs from deletion and increased the number of memory CD8 T cells. Thus, the cumulative strength of convergent signals from signaling molecules such as TCR, costimulatory molecules, and cytokine receptors governs the magnitude of Akt activation, which in turn controls the generation of long-lived memory cells. These findings suggest that therapeutic modulation of Akt might be a strategy to augment vaccine-induced immunity.