TCR Signal Transduction in Antigen-Specific Memory CD8 T Cells (original) (raw)
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Functional differences between memory and naive CD8 T cells
Proceedings of the National Academy of Sciences, 1999
To determine how murine memory and naive T cells differ, we generated large numbers of long-lived memory CD8 + T cells and compared them to naive cells expressing the same antigen-specific receptor (T cell receptor; TCR). Although both populations expressed similar levels of TCR and CD8, on antigen stimulation in vitro memory T cells down-regulated their TCR faster and more extensively and secreted IFN-γ and IL-2 faster than naive T cells. Memory cells were also larger, and when freshly isolated from mice they contained perforin and killed target cells without having to be restimulated. They further differed from naive cells in requiring IL-15 for proliferation and in having a greater tendency to undergo apoptosis in vitro . On antigen stimulation in vivo , however, they proliferated more rapidly than naive cells. These findings suggest that, unlike naive T cells, CD8 memory T cells are intrinsically programmed to rapidly express their effector functions in vivo without having to un...
TCR Signaling in T Cell Memory
Frontiers in Immunology, 2015
T cell memory plays a critical role in our protection against pathogens and tumors. The antigen and its interaction with the T cell receptor (TCR) is one of the initiating elements that shape T cell memory together with inflammation and costimulation. Over the last decade, several transcription factors and signaling pathways that support memory programing have been identified. However, how TCR signals regulate them is still poorly understood. Recent studies have shown that the biochemical rules that govern T cell memory, strikingly, change depending on the TCR signal strength. Furthermore, TCR signal strength regulates the input of cytokine signaling, including pro-inflammatory cytokines. These highlight how tailoring antigenic signals can improve immune therapeutics. In this review, we focus on how TCR signaling regulates T cell memory and how the quantity and quality of TCR-peptide-MHC interactions impact the multiple fates a T cell can adopt in the memory pool.
Constitutive Lck Activity Drives Sensitivity Differences between CD8+ Memory T Cell Subsets
Journal of immunology (Baltimore, Md. : 1950), 2016
CD8(+) T cells develop increased sensitivity following Ag experience, and differences in sensitivity exist between T cell memory subsets. How differential TCR signaling between memory subsets contributes to sensitivity differences is unclear. We show in mouse effector memory T cells (TEM) that >50% of lymphocyte-specific protein tyrosine kinase (Lck) exists in a constitutively active conformation, compared with <20% in central memory T cells (TCM). Immediately proximal to Lck signaling, we observed enhanced Zap-70 phosphorylation in TEM following TCR ligation compared with TCM Furthermore, we observed superior cytotoxic effector function in TEM compared with TCM, and we provide evidence that this results from a lower probability of TCM reaching threshold signaling owing to the decreased magnitude of TCR-proximal signaling. We provide evidence that the differences in Lck constitutive activity between CD8(+) TCM and TEM are due to differential regulation by SH2 domain-containing...
CD8 T cell memory: it takes all kinds
Frontiers in immunology, 2012
Understanding the mechanisms that regulate the differentiation and maintenance of CD8(+) memory T cells is fundamental to the development of effective T cell-based vaccines. Memory cell differentiation is influenced by the cytokines that accompany T cell priming, the history of previous antigen encounters, and the tissue sites into which memory cells migrate. These cues combine to influence the developing CD8(+) memory pool, and recent work has revealed the importance of multiple transcription factors, metabolic molecules, and surface receptors in revealing the type of memory cell that is generated. Paired with increasingly meticulous subsetting and sorting of memory populations, we now know the CD8(+) memory pool to be phenotypically and functionally heterogeneous in nature. This includes both recirculating and tissue-resident memory populations, and cells with varying degrees of inherent longevity and protective function. These data point to the importance of tailored vaccine desi...
Immunology, 2005
Memory T-cell responses are faster and more robust than those of their naïve counterparts. The mechanisms by which memory T cells respond better to subsequent antigenic exposure remain unresolved. A portion of the more rapid response is undoubtedly the result of the increased frequency of antigen-specific cells. In addition, there are also differences in the cells themselves with respect to their requirements for costimulation and the apparent avidity of the T cells. We used major histocompatibility complex (MHC) class I tetramers to stimulate T cells to focus on the interaction of T-cell receptor (TCR)/MHC and CD8 in the absence of other molecules that are present on cell surfaces and so contribute to the activation of T cells by undefined mechanisms. Mutated MHC class I tetramers that are unable to engage CD8 were used to investigate the role of CD8 engagement in memory cell activation. Either wild-type tetramers or tetramers carrying the mutation were used to stimulate both memory and naïve TCR transgenic T cells in vitro. Surprisingly, like naïve cells, memory CD8 + T cells required CD8 engagement for calcium mobilization and optimum proliferation. In contrast, the requirements for cytokine production differed. Unlike naive cells, memory cells were able to produce cytokine in the absence of CD8 engagement. This suggests both a CD8dependent pathway for early events and a CD8-independent pathway for cytokine production in memory cells.