Quick to remember, slow to forget: rapid recall responses of memory CD8+ T cells

Abstract

The functional roles of memory B and T lymphocytes underlie the phenomenal success of prophylactic vaccinations, which have decreased morbidities and mortalities from infectious diseases globally over the last 50 years. However, it is becoming increasingly appreciated that memory cells are also capable of mediating the pathology associated with autoimmune disorders and transplant rejection, and may pose a significant barrier to future clinical advancement in immunoregulation. Therefore, understanding the unique properties of memory lymphocytes (as compared to their naive precursors) is a major area of investigation. Here, we focus on one of those singular properties of memory T cells (T M )-rapid recall. As will be discussed in more detail, rapid recall refers to the ability of quiescent T M cells to efficiently and robustly express 'effector functions' following stimulation. Studies that have advanced our understanding of T M cells' rapid recall using CD4 + T cells have been expertly reviewed elsewhere [1], so we will focus primarily on studies of CD8 + T cells. We will first review the different ways that CD8 + T M cells can be generated, followed by discussing how this influences their functional properties in the settings of immune protection and pathology. Then, rapid recall ability will be discussed, with emphasis placed on what is currently known about the mechanisms that underlie this unique property of T M cells.

CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability

“…Consistent with previous studies (3,4,33), we show here that T M cells are intrinsically different as they proliferate faster and make more cytokine after activation in vitro. This more ready-to-respond state of T M cells has been attributed to several intrinsic differences such as an "open" chromatin conformation of cytokine genes, altered transcription profiles, and enhanced activity of proximal TCR signaling components (1,2). We now show here that rapid proliferation and engagement of glycolysis by T M cells after activation requires mitochondrial ATP to enable optimal HK function.…”

“…Although quantitative differences in Ag-specific T N and T M cells can contribute to the superior protection conferred by T M cells upon reinfection, studies where equal cell numbers were transferred into mice have shown that these cells respond with distinct kinetics (1,3,5,29,30). T M cells enter the cell cycle earlier and proliferate faster than T N cells after activation (3)(4)(5).…”

“…Although both T N and T M cells acquire effector functions, a noted characteristic of T M cells is their ability to respond more rapidly than T N cells to Ag (1)(2)(3)(4). Several factors underlie the accelerated recall response of T M cells.…”

Role of antigen persistence and dose for CD4+T-cell exhaustion and recovery

“…However, memory cells produced all three cytokines (Fig. 4B, treatment 1) as rapid secretion in response to brief stimulation with PMA and IM is their key feature (24,25). Our data suggest differential susceptibilities of these three cytokines to suppression by persistent antigen, probably via stepwise impairment by, or differential recovery from, antigenic exhaustion.…”

Decreased Diacylglycerol Metabolism Enhances ERK Activation and Augments CD8+ T Cell Functional Responses

“…3A, lower panels), CD3, TCR, CD25, CD69, or the IL7 receptor CD127 (data not shown). Expression of high levels of CD44 on lymphocytes marks cells that are capable of generating rapid functional responses, such as cytokine production, in response to TCR stimulation (24). The changes that confer rapid functional responsiveness in CD44 high cells are primarily at the level of gene transcription, downstream of the TCR signal machinery (25).…”