Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates

It has been proposed that two different antigen-experienced T cell subsets may be distinguishable by their preferential ability to home to lymphoid organs (central memory cells) or nonlymphoid tissues (effector memory/effector cells). We have shown recently that murine antigen-primed CD8+ T cells cultured in interleukin (IL)-15 (CD8IL-15) resemble central memory cells in phenotype and function. In contrast, primed CD8+ T cells cultured in IL-2 (CD8IL-2) become cytotoxic effector cells. Here, the migratory behavior of these two subsets was investigated. Naive, CD8IL-15 cells and, to a lesser degree, CD8IL-2 cells localized to T cell areas in the spleen, but only naive and CD8IL-15 cells homed to lymph nodes (LNs) and Peyer's patches. Intravital microscopy of peripheral LNs revealed that CD8IL-15 cells, but not CD8IL-2 cells, rolled and arrested in high endothelial venules (HEVs). Migration of CD8IL-15 cells to LNs depended on L-selectin and required chemokines that bind CC chemokine receptor (CCR)7. Both antigen-experienced populations, but not naive T cells, responded to inflammatory chemokines and accumulated at sites of inflammation. However, CD8IL-2 cells were 12 times more efficient in migrating to inflamed peritoneum than CD8IL-15 cells. Furthermore, CD8IL-15 cells proliferated rapidly upon reencounter with antigen at sites of inflammation. Thus, central memory-like CD8IL-15 cells home avidly to lymphoid organs and moderately to sites of inflammation, where they mediate rapid recall responses, whereas CD8IL-2 effector T cells accumulate in inflamed tissues, but are excluded from most lymphoid organs.

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Faculty Opinions recommendation of T cell memory. Resident memory CD8 T cells trigger protective innate and adaptive immune responses.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718549286.793500135 ◽

2014 ◽

Author(s):

Torben Lund

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Cd8 T Cells ◽

T Cell Memory ◽

Adaptive Immune Responses ◽

Cell Memory ◽

Memory Cd8 T Cells ◽

Adaptive Immune

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Mitochondrial activity regulates T cell memory, self renewal and anti tumor function in CD8+ T cells

Journal for ImmunoTherapy of Cancer ◽

10.1186/2051-1426-1-s1-o11 ◽

2013 ◽

Vol 1 (S1) ◽

Cited By ~ 1

Author(s):

Madhusudhanan Sukumar ◽

Jie Liu ◽

Joseph Crompton ◽

Mahadev Rao ◽

Yun Ji ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

T Cell Memory ◽

Mitochondrial Activity ◽

Cell Memory ◽

Self Renewal

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HIV-specific CD8 T cells express low levels of IL-7Rα: Implications for HIV-specific T cell memory

Virology ◽

10.1016/j.virol.2006.06.017 ◽

2006 ◽

Vol 353 (2) ◽

pp. 366-373 ◽

Cited By ~ 38

Author(s):

E. John Wherry ◽

Cheryl L. Day ◽

Rika Draenert ◽

Joseph D. Miller ◽

Photini Kiepiela ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

T Cell Memory ◽

Cell Memory ◽

Low Levels

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N-ras couples antigen receptor signaling to Eomesodermin and to functional CD8+ T cell memory but not to effector differentiation

Journal of Experimental Medicine ◽

10.1084/jem.20112495 ◽

2013 ◽

Vol 210 (7) ◽

pp. 1463-1479 ◽

Cited By ~ 19

Author(s):

Salvador Iborra ◽

Manuel Ramos ◽

David M. Arana ◽

Silvia Lázaro ◽

Francisco Aguilar ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cd8 T Cell ◽

Small Gtpase ◽

T Cell Memory ◽

Cell Memory ◽

Cd8 T Cell Memory

Signals from the TCR that specifically contribute to effector versus memory CD8+ T cell differentiation are poorly understood. Using mice and adoptively transferred T lymphocytes lacking the small GTPase N-ras, we found that N-ras–deficient CD8+ T cells differentiate efficiently into antiviral primary effectors but have a severe defect in generating protective memory cells. This defect was rescued, although only partly, by rapamycin-mediated inhibition of mammalian target of rapamycin (mTOR) in vivo. The memory defect correlated with a marked impairment in vitro and in vivo of the antigen-mediated early induction of T-box transcription factor Eomesodermin (Eomes), whereas T-bet was unaffected. Besides N-ras, early Eomes induction in vitro required phosphoinositide 3-kinase (PI3K)–AKT but not extracellular signal-regulated kinase (ERK) activation, and it was largely insensitive to rapamycin. Consistent with N-ras coupling Eomes to T cell memory, retrovirally enforced expression of Eomes in N-ras–deficient CD8+ T cells effectively rescued their memory differentiation. Thus, our study identifies a critical role for N-ras as a TCR-proximal regulator of Eomes for early determination of the CD8+ T cell memory fate.

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Regulation of Memory CD8 T-Cell Differentiation by Cyclin-Dependent Kinase Inhibitor p27Kip1

Molecular and Cellular Biology ◽

10.1128/mcb.01045-09 ◽

2010 ◽

Vol 30 (21) ◽

pp. 5145-5159 ◽

Cited By ~ 16

Author(s):

Anju Singh ◽

Anna Jatzek ◽

Erin Hemmila Plisch ◽

Rajini Srinivasan ◽

John Svaren ◽

...

Keyword(s):

Cell Cycle ◽

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Kinase Inhibitor ◽

Cd8 T Cell ◽

T Cell Memory ◽

Cell Memory ◽

Memory Cd8 T Cells ◽

Cyclin Dependent Kinase Inhibitor

ABSTRACT Induction of potent T-cell memory is the goal of vaccinations, but the molecular mechanisms that regulate the formation of memory CD8 T cells are not well understood. Despite the recognition that controls of cellular proliferation and apoptosis govern the number of memory T cells, the cell cycle regulatory mechanisms that control these key cellular processes in CD8 T cells during an immune response are poorly defined. Here, we have identified the cyclin-dependent kinase inhibitor p27Kip1 as a critical regulator of the CD8 T-cell homeostasis at all phases of the T-cell response to an acute viral infection in mice. By acting as a timer for cell cycle exit, p27Kip1 curtailed the programmed expansion of interleukin-2-producing memory precursors and markedly limited the magnitude and quality of CD8 T-cell memory. In the absence of p27Kip1, CD8 T cells showed superior recall responses shortly after vaccination with recombinant Listeria monocytogenes. Additionally, we show that p27Kip1 constrains proliferative renewal of memory CD8 T cells, especially of the effector memory subset. These findings provide critical insights into the cell cycle regulation of CD8 T-cell homeostasis and suggest that modulation of p27Kip1 could bolster vaccine-induced T-cell memory and protective immunity.

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Inhibiting BRD4 to generate BETter T cell memory

Journal of Experimental Medicine ◽

10.1084/jem.20210877 ◽

2021 ◽

Vol 218 (8) ◽

Author(s):

Moujtaba Y. Kasmani ◽

Weiguo Cui

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Critical Role ◽

Effector Function ◽

T Cell Memory ◽

Cell Memory

BRD4 is a bromodomain-containing protein that binds acetylated histones to regulate transcription. In this issue of JEM, Milner et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20202512) show that BRD4 plays a critical role in the effector function of CD8 T cells responding to infection and cancer.

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Differentiation of exhausted CD8 T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory

10.1101/2021.04.03.437705 ◽

2021 ◽

Author(s):

Pierre Tonnerre ◽

David Wolski ◽

Sonu Subudhi ◽

Jihad Al-Jabban ◽

Ruben C. Hoogeveen ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Hcv Infection ◽

Viral Escape ◽

T Cell Memory ◽

T Cell Exhaustion ◽

Cell Memory ◽

Cell Exhaustion ◽

Antigen Removal

T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Analysis of antigen-specific CD8+ T cells before and after antigen removal in human hepatitis C virus (HCV) infection confirmed pervasive phenotypic, functional, and transcriptional differences between exhausted and memory CD8+ T cells. After viral cure, we observed broad phenotypic and transcriptional changes in clonally stable exhausted T-cell populations suggesting differentiation towards a memory-like profile. However, functionally, the cells showed little improvement and critical transcriptional regulators remained in the exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for shorter periods of time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved acute HCV infection. Thus, duration of T cell stimulation impacts the ability to recover from exhaustion, as antigen removal after long-term T cell exhaustion is insufficient for the development of key T cell memory characteristics.

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Systemic CD8 T-Cell Memory Response to a Salmonella Pathogenicity Island 2 Effector Is Restricted to Salmonella enterica Encountered in the Gastrointestinal Mucosa

Infection and Immunity ◽

10.1128/iai.01905-06 ◽

2007 ◽

Vol 75 (6) ◽

pp. 2708-2716 ◽

Cited By ~ 9

Author(s):

Jessica Jones-Carson ◽

Bruce D. McCollister ◽

Eric T. Clambey ◽

Andrés Vázquez-Torres

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cd8 T Cell ◽

Central Memory ◽

Effector Memory ◽

Memory Cd8 T Cells ◽

Memory Response ◽

Central Memory Cells ◽

Systemic Memory

ABSTRACT To better understand the evolution of a systemic memory response to a mucosal pathogen, we monitored antigen-specific OT1 CD8 T-cell responses to a fusion of the SspH2 protein and the peptide SIINFEKL stably expressed from the chromosome of Salmonella enterica and loaded into the class I pathway of antigen presentation of professional phagocytes through the Salmonella pathogenicity island 2 type III secretion system (TTSS). This strategy has revealed that effector memory CD8 T cells with low levels of CD62L expression (CD62Llow) are maintained in systemic sites months after vaccination in response to low-grade infections with Salmonella. However, the CD8 T-cell pool eventually declines. Low numbers of central memory cells surviving after prolonged resting from an antigen encounter can nevertheless reconstitute the systemic effector memory pool in a route-specific recall response to cognate antigens encountered in the gut. Accordingly, populations of CD62Lhigh interleukin-7 receptor-positive progenitor central memory cells grafted into naïve mice expand in response to orally administered Salmonella expressing the chromosomal translational fusion of sspH2 and the sequence encoding the SIINFEKL peptide but fail to proliferate following systemic stimulation. Moreover, populations of systemic memory CD8 T cells restricted to Salmonella in oral vaccines selectively expand in response to cognate antigens presented by cells isolated from mesenteric lymph nodes (MLN). Together, these findings have revealed the imprinting of systemic CD8 central memory T-cell recall responses against enteropathogens by MLN. MLN restriction represents a novel mechanism by which systemic CD8 T-cell immunity is confined to periods of high risk for extraintestinal dissemination.

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