scholarly journals Secondary memory CD8+ T cells are more protective but slower to acquire a central–memory phenotype

2006 ◽  
Vol 203 (4) ◽  
pp. 919-932 ◽  
Author(s):  
Ali Jabbari ◽  
John T. Harty
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Central Memory ◽  
Secondary Memory ◽  
Memory Cd8 T Cells ◽  
Memory Phenotype ◽  
Cd8 T Cell Memory ◽  
Central Memory Phenotype

The formation of memory CD8 T cells is an important goal of vaccination. However, although widespread use of booster immunizations in humans generates secondary and tertiary CD8 T cell memory, experimental data are limited to primary CD8 T cell memory. Here, we show that, compared with primary memory CD8 T cells, secondary memory CD8 T cells exhibit substantially delayed conversion to a central–memory phenotype, as determined by CD62L expression and interleukin (IL)-2 production. This delayed conversion to a central–memory phenotype correlates with reduced basal proliferation and responsiveness to IL-15, although in vitro coculture with a high concentration of IL-15 is capable of inducing proliferation and CD62L upregulation. Functionally, secondary memory CD8 T cells are more protective in vivo on a per cell basis, and this may be explained by sustained lytic ability. Additionally, secondary memory CD8 T cells are more permissive than primary memory CD8 T cells for new T cell priming in lymph nodes, possibly suggesting a mechanism of replacement for memory T cells. Thus, primary and secondary memory CD8 T cells are functionally distinct, and the number of encounters with antigen influences memory CD8 T cell function.

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

2007 ◽  
Vol 75 (6) ◽  
pp. 2708-2716 ◽  
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.

scholarly journals Combination Adjuvants Affect the Magnitude of Effector-Like Memory CD8 T Cells and Protection against Listeriosis

2021 ◽  
Author(s):  
Woojong Lee ◽  
Autumn Larsen ◽  
Brock Kingstad-Bakke ◽  
Chandranaik B. Marinaik ◽  
M. Suresh
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Protective Immunity ◽  
Cd8 T Cell ◽  
T Cell Memory ◽  
Memory Cd8 T Cells ◽  
Cross Presentation ◽  
Nano Emulsion ◽  
Cd8 T Cell Memory

Development of T-cell-based subunit protein vaccines against diseases, such as tuberculosis and malaria, remains a challenge for immunologists. Here, we have identified a nano-emulsion adjuvant Adjuplex (ADJ), which enhanced dendritic cell (DC) cross-presentation and elicited effective memory T cell-based immunity to Listeria monocytogenes (LM). We further evaluated whether cross-presentation induced by ADJ, can be combined with the immunomodulatory effects of TLR agonists (CpG or glucopyranosyl lipid adjuvant [GLA]) to evoke systemic CD8 T cell-based immunity to LM. Mechanistically, vaccination with ADJ, alone or in combination with CpG or GLA augmented activation and antigen uptake by CD103+ migratory and CD8α+ resident DCs and up-regulated CD69 expression on B and T lymphocytes in vaccine-draining lymph nodes. By engaging basic leucine zipper ATF-like transcription factor 3-dependent cross-presenting DCs, ADJ potently elicited effector CD8 T cells that differentiated into granzyme B-expressing CD27LO effector-like memory CD8 T cells, which provided effective immunity to LM in spleen and liver. CpG or GLA alone did not elicit effector-like memory CD8 T cells and induced moderate protection in spleen, but not in the liver. Surprisingly, combining CpG or GLA with ADJ reduced the number of ADJ-induced memory CD8 T cells and compromised protective immunity to LM, especially in the liver. Taken together, data presented in this manuscript provides a glimpse of protective CD8 T cell memory differentiation induced by a nano-emulsion adjuvant and demonstrates the unexpected negative effects of TLR signaling on the magnitude of CD8 T cell memory and protective immunity to LM, a model intracellular pathogen.

scholarly journals Subunit Vaccine-Elicited Effector-Like Memory CD8 T Cells Protect Against Listeriosis

2020 ◽  
Author(s):  
Woojong Lee ◽  
Autumn Larsen ◽  
Brock Kingstad-Bakke ◽  
M. Suresh
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Protective Immunity ◽  
Cd8 T Cell ◽  
T Cell Memory ◽  
Memory Cd8 T Cells ◽  
Cell Immunity ◽  
Nano Emulsion ◽  
Cd8 T Cell Memory

AbstractDevelopment of T-cell-based subunit protein vaccines against diseases, such as AIDS, tuberculosis and malaria remains a challenge for immunologists. Here, we have evaluated whether cross-presentation induced by nanoemulsion adjuvant Adjuplex (ADJ), can be combined with the immunomodulatory effects of TLR agonists (CpG or glucopyranosyl lipid adjuvant [GLA]) to evoke protective systemic CD8 T cell-based immunity to Listeria monocytogenes (LM). Vaccination with ADJ, alone or in combination with CpG or GLA augmented activation and antigen uptake by migratory and resident dendritic cells and up-regulated CD69 expression on B and T lymphocytes in draining lymph nodes. By virtue of its ability to engage BATF3-dependent cross-presenting DCs, ADJ potently elicited effector CD8 T cells that differentiated into a distinct subset of granzyme B-expressing CD27LO effector-like memory CD8 T cells, which provided highly effective immunity to LM in spleen and liver. CpG or GLA alone did not elicit effector-like memory CD8 T cells and induced moderate protection in spleen, but not in the liver. Surprisingly, combining CpG or GLA with ADJ limited the magnitude of ADJ-induced CD8 T cell memory and compromised protective immunity to LM, especially in the liver. Taken together, data presented in this manuscript provides a glimpse of protective CD8 T cell memory differentiation induced by a nano-emulsion adjuvant and demonstrates the unexpected negative effects of TLR signaling on the magnitude of CD8 T cell memory and protective immunity to listeriosis.ImportanceTo date, the most effective vaccines primarily provide protection by eliciting neutralizing antibodies, while development of T-cell-based subunit vaccines against infectious diseases, such as tuberculosis and malaria, remains a challenge for immunologists. Axiomatically, engagement of multiple innate immune receptors early in the response might be key to programming effective immunity. Hence, there is an impetus to develop combination adjuvants that engage multiple innate signaling pathways and additionally promote cross-presentation to stimulate CD8 T-cell immunity. Here, we show that a nano-emulsion adjuvant ADJ alone elicits effector-like memory CD8 T cells and provides highly effective immunity to listeriosis; combining ADJ with TLR agonists, including CpG and GLA, compromised T cell immunity to LM. In summary, this study provided fundamental insights into the effects of combining innate immune signaling with nano-emulsion adjuvants on memory T cell differentiation and protective immunity. These findings are expected to have implications in the use of combination adjuvants to develop subunit vaccines that engender systemic CD8 T-cell immunity to intracellular pathogens.

Defective Central Memory CD8+ T Cell Differentiation in the Absence of Eomesodermin.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2662-2662
Author(s):  
Arnob Banerjee ◽  
Scott M. Gordon ◽  
Andrew M. Intlekofer ◽  
E. John Wherry ◽  
Steven L. Reiner
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Dna Binding ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Central Memory ◽  
T Cell Differentiation ◽  
Memory Cd8 T Cells ◽  
Memory Differentiation

Abstract Abstract 2662 Poster Board II-638 The differentiation of central memory CD8+ T cells after vaccination or primary pathogen encounter is critical for the establishment of long-lasting protection against pathogens including intracellular infectious organisms and malignancies. Unfortunately, the mechanisms of immune memory establishment are unclear, preventing the development of effective vaccines to many emerging pathogens. Naïve CD8+ T cells responding to intracellular pathogens undergo rounds of cell division and progressive differentiation to give rise to terminally differentiated effector cells and memory cells to provide acute and long-lasting immunity, respectively. T-bet and Eomesodermin (Eomes), key transcription factors in this differentiation, share significant DNA binding domain sequence and functional homology, although their distinct expression patterns and non-DNA binding domains suggest potential non-redundant functions. T-bet drives effector and effector-memory differentiation, suppressing the formation of long-lasting central memory CD8+ T cells. We now show that CD8+ T cells responding to acute infection with the lymphocytic choriomeningitis virus (LCMV) display significant heterogeneity in the relative expression levels of T-bet and Eomes on a single cell level. Using mice with a tissue specific deletion of Eomes in T cells, we show defective central-memory differentiation in CD8+ T cells lacking Eomes after infection with LCMV. We observe defects in both long-term persistence and re-expansion on re-challenge, two defining characteristics of central-memory T cells, in memory CD8+ T cells lacking Eomes. These results demonstrate that, in direct contrast to T-bet, Eomes promotes central-memory CD8+ T cell differentiation. Thus, the balance of T-bet and Eomes expression may determine the propensity for CD8+ T cell terminal effector differentation versus long-lived memory differentiation. Our findings demonstrate a crucial role for Eomes in the differentiation of pathogen specific central memory CD8+ T cells which can provide life-long immune protection. Disclosures: No relevant conflicts of interest to declare.

Expanded CLL CD8+ T-Cells Are Driven Into a Senescent KLRG1+ Effector Memory Phenotype

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 913-913
Author(s):  
Joachim Rudolf Göthert ◽  
Lewin Eisele ◽  
Ludger Klein-Hitpass ◽  
Stefanie Weber ◽  
Anja Führer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
Peritoneal Cavity ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Effector Memory ◽  
Cell Compartment ◽  
Memory Cd8 T Cells ◽  
Memory Phenotype

Abstract Abstract 913 Altered numbers and functions of T-cells have previously been demonstrated in chronic lymphocytic leukemia (CLL) patients. However, dynamics and specific T-cell subset alterations have not been studied in great detail. Therefore, we determined numbers of blood lymphocyte subsets of CLL patients in a longitudinal manner. We found that dynamic expansions of the peripheral blood CD4+ and CD8+ T-cell numbers were consistently associated with a progressively increasing CLL leukemic compartment. Additionally, we performed gene expression profiling (GEP) of blood CD3+ T-cells of CLL patients and normal donors. We identified a list of 135 genes that had significantly increased expression and 11 genes that had significantly decreased expression in CLL T-cells. The up-regulated genes included killer cell lectin-like receptor familiy members KLRA1, KLRC2, KLRD1 (CD94), KLRK1 and KLRF1 as well as CD244 (NK-cell receptor 2B4), CD160 (NK cell receptor BY55), PRF1 (perforin 1) and CRTAM (class-I MHC-restricted T-cell associated molecule). These up-regulated genes are known to be preferentially expressed by CD8+ T-cells with an effector memory phenotype. We used Gene Set Enrichment Analysis (GSEA) to investigate whether CLL T-cell genes correlate with a previously published gene expression signature of effector memory CD8+ T-cells (Willinger et al., Journal of Immunolgy 175[9], 2005). This analysis revealed a highly significant enrichment of CLL T-cell genes within the effector memory CD8+ T-cell signature (p<0.0001, FDR q<0.001). Next, we studied the CLL CD8+ T-cell compartment using flow cytometry. As already implied by GEP and GSEA, the flow cytometric analysis revealed a relative shift of subsets within the CD8+ T-cell compartment. Compared to normal donors we observed a decreased proportion of naïve CD8+ T-cells (CD45RA+CCR7+) and an increased proportion of CD8+ effector memory cells (CD45RA-CCR7-) in the CLL cohort as compared to normal donor controls. When absolute cell numbers were calculated on the basis of these results it became evident that the elevation in the absolute number of overall CD8+ T-cells in CLL was primarily attributable to the expansion of the effector memory subset of CD8+ T-cells. Subsequently, we compared the killer cell lectin-like receptor G1 (KLRG1) surface expression of CLL and normal donor CD8+ effector memory T-cells. KLRG1 marks cells, which have undergone extensive proliferation and lack replicative potential. We observed that the absolute increments of effector memory CD8+ T-cells in human CLL patients were mainly due to the expansion of the senescent KLRG1 expressing subset of cells. In order to test whether the CD8+ effector memory expansion is a general biologic CLL phenomenon we studied the CD8+ T-cell compartment of a murine transgenic CLL model (7-month-old TCL1 transgenic mice). It was previously described that TCL1 CD5+CD19+ B-cell hyperplasia first emerges in the peritoneal cavity of TCL1 transgenic mice. Therefore, we specifically studied how CD8+ T-cell subsets respond to arising CLL in the peritoneal cavity of TCL1 transgenic mice. Strikingly, we found that our observation of effector memory shifted CD8+ T-cells in human CLL was phenocopied in the peritoneal cavity of TCL1 transgenic mice. The proportion of peritoneal naïve CD8+ T-cells (CD62L+CD44-) was significantly decreased while the proportion of CD8+ effector memory T-cells (CD62L-CD44+) was significantly increased. Moreover, we observed a more than two-fold increase of KLRG1+ effector memory CD8+ T-cells in the peripheral blood and spleens of TCL1 transgenic mice compared to wild-type controls. In summary, we were able to show that human as well as mouse CLL CD8+ T-cells are driven into a senescent effector memory phenotype. This might significantly contribute to CLL immune dysfunction and might additionally represent an important component of the CLL microenvironment. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Immunodominant Cytomegalovirus Epitopes Suppress Subdominant Epitopes in the Generation of High-Avidity CD8 T Cells

Pathogens ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 956
Author(s):  
Kirsten Freitag ◽  
Sara Hamdan ◽  
Matthias J. Reddehase ◽  
Rafaela Holtappels
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Escape ◽  
Cd8 T Cell ◽  
Antigenic Drift ◽  
Murine Cytomegalovirus ◽  
High Avidity ◽  
Infected Cells ◽  
Cd8 T Cell Memory

CD8+ T-cell responses to pathogens are directed against infected cells that present pathogen-encoded peptides on MHC class-I molecules. Although natural responses are polyclonal, the spectrum of peptides that qualify for epitopes is remarkably small even for pathogens with high coding capacity. Among those few that are successful at all, a hierarchy exists in the magnitude of the response that they elicit in terms of numbers of CD8+ T cells generated. This led to a classification into immunodominant and non-immunodominant or subordinate epitopes, IDEs and non-IDEs, respectively. IDEs are favored in the design of vaccines and are chosen for CD8+ T-cell immunotherapy. Using murine cytomegalovirus as a model, we provide evidence to conclude that epitope hierarchy reflects competition on the level of antigen recognition. Notably, high-avidity cells specific for non-IDEs were found to expand only when IDEs were deleted. This may be a host’s back-up strategy to avoid viral immune escape through antigenic drift caused by IDE mutations. Importantly, our results are relevant for the design of vaccines based on cytomegaloviruses as vectors to generate high-avidity CD8+ T-cell memory specific for unrelated pathogens or tumors. We propose the deletion of vector-encoded IDEs to avoid the suppression of epitopes of the vaccine target.

scholarly journals Superior Protective Immunity against Murine Listeriosis by Combined Vaccination with CpG DNA and Recombinant Salmonella enterica Serovar Typhimurium

2009 ◽  
Vol 77 (12) ◽  
pp. 5501-5508 ◽  
Author(s):  
Christina Berchtold ◽  
Klaus Panthel ◽  
Stefan Jellbauer ◽  
Brigitte Köhn ◽  
Elisabeth Roider ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Salmonella Enterica ◽  
Protective Immunity ◽  
Cd8 T Cell ◽  
Cpg Dna ◽  
Memory Cd8 T Cells ◽  
Type Iii ◽  
Serovar Typhimurium

ABSTRACT Preexisting antivector immunity can severely compromise the ability of Salmonella enterica serovar Typhimurium live vaccines to induce protective CD8 T-cell frequencies after type III secretion system-mediated heterologous protein translocation in orally immunized mice. To circumvent this problem, we injected CpG DNA admixed to the immunodominant p60217-225 peptide from Listeria monocytogenes subcutaneously into BALB/c mice and coadministered a p60-translocating Salmonella strain by the orogastric route. The distribution of tetramer-positive p60217-225-specific effector and memory CD8 T cells was analyzed by costaining of lymphocytes with CD62L and CD127. In contrast to the single oral application of recombinant Salmonella or single immunization with CpG and p60, in the spleens from mice immunized with a combination of both vaccine types a significantly higher level of p60-specific CD8 T cells with a predominance of the effector memory T-cell subset was detected. In vivo protection studies revealed that this CD8 T-cell population conferred sterile protective immunity against a lethal infection with L. monocytogenes. However, p60-specific central memory CD8 T cells induced by single vaccination with CpG and p60 were not able confer effective protection against rapidly replicating intracellular Listeria. In conclusion, we provide compelling evidence that the combination of Salmonella type III-mediated antigen delivery and CpG immunization is an attractive novel vaccination strategy to modulate CD8 differentiation patterns toward distinct antigen-specific T-cell subsets with favorable protective capacities.

scholarly journals Human memory CD8 T cell effector potential is epigenetically preserved during in vivo homeostasis

2017 ◽  
Vol 214 (6) ◽  
pp. 1593-1606 ◽  
Author(s):  
Hossam A. Abdelsamed ◽  
Ardiana Moustaki ◽  
Yiping Fan ◽  
Pranay Dogra ◽  
Hazem E. Ghoneim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Human Memory ◽  
Memory Cd8 T Cells ◽  
Memory Cd8 T Cell ◽  
Cell Effector

Antigen-independent homeostasis of memory CD8 T cells is vital for sustaining long-lived T cell–mediated immunity. In this study, we report that maintenance of human memory CD8 T cell effector potential during in vitro and in vivo homeostatic proliferation is coupled to preservation of acquired DNA methylation programs. Whole-genome bisulfite sequencing of primary human naive, short-lived effector memory (TEM), and longer-lived central memory (TCM) and stem cell memory (TSCM) CD8 T cells identified effector molecules with demethylated promoters and poised for expression. Effector-loci demethylation was heritably preserved during IL-7– and IL-15–mediated in vitro cell proliferation. Conversely, cytokine-driven proliferation of TCM and TSCM memory cells resulted in phenotypic conversion into TEM cells and was coupled to increased methylation of the CCR7 and Tcf7 loci. Furthermore, haploidentical donor memory CD8 T cells undergoing in vivo proliferation in lymphodepleted recipients also maintained their effector-associated demethylated status but acquired TEM-associated programs. These data demonstrate that effector-associated epigenetic programs are preserved during cytokine-driven subset interconversion of human memory CD8 T cells.

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