CCR7 expression alters memory CD8 T-cell homeostasis by regulating occupancy in IL-7– and IL-15–dependent niches

C-C receptor 7 (CCR7) is important to allow T cells and dendritic cells to migrate toward CCL19- and CCL21-producing cells in the T-cell zone of the spleen and lymph nodes. The role of this chemokine receptor in regulating the homeostasis of effector and memory T cells during acute viral infection is poorly defined, however. In this study, we show that CCR7 expression alters memory CD8 T-cell homeostasis following lymphocytic choriomeningitis virus infection. Greater numbers of CCR7-deficient memory T cells were formed and maintained compared with CCR7-sufficient memory T cells, especially in the lung and bone marrow. The CCR7-deficient memory T cells also displayed enhanced rates of homeostatic turnover, which may stem from increased exposure to IL-15 as a consequence of reduced exposure to IL-7, because removal of IL-15, but not of IL-7, normalized the numbers of CCR7-sufficient and CCR7-deficient memory CD8 T cells. This result suggests that IL-15 is the predominant cytokine supporting augmentation of the CCR7−/− memory CD8 T-cell pool. Taken together, these data suggest that CCR7 biases memory CD8 T cells toward IL-7–dependent niches over IL-15–dependent niches, which provides insight into the homeostatic regulation of different memory T-cell subsets.

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Dendritic cells drive memory CD8 T-cell homeostasis via IL-15 transpresentation

Blood ◽

10.1182/blood-2008-05-156307 ◽

2008 ◽

Vol 112 (12) ◽

pp. 4546-4554 ◽

Cited By ~ 70

Author(s):

Spencer W. Stonier ◽

Lisa J. Ma ◽

Eliseo F. Castillo ◽

Kimberly S. Schluns

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cd8 T Cell ◽

T Cell Homeostasis ◽

Cell Homeostasis ◽

Memory Cd8 T Cells ◽

Specific Memory ◽

Memory Cd8 T Cell

AbstractInterleukin-15 (IL-15) is crucial for the development of naive and memory CD8 T cells and is delivered through a mechanism called transpresentation. Previous studies showed that memory CD8 T cells require IL-15 transpresentation by an as yet unknown cell of hematopoietic origin. We hypothesized that dendritic cells (DCs) transpresent IL-15 to CD8 T cells, and we examined this by developing a transgenic model that limits IL-15 transpresentation to DCs. In this study, IL-15 transpresentation by DCs had little effect on restoring naive CD8 T cells but contributed to the development of memory-phenotype CD8 T cells. The generation of virus-specific, memory CD8 T cells was partially supported by IL-15Rα+ DCs through the preferential enhancement of a subset of KLRG-1+CD27− CD8 T cells. In contrast, these DCs were largely sufficient in driving normal homeostatic proliferation of established memory CD8 T cells, suggesting that memory CD8 T cells grow more dependent on IL-15 transpresentation by DCs. Overall, our study clearly supports a role for DCs in memory CD8 T-cell homeostasis but also provides evidence that other hematopoietic cells are involved in this function. The identification of DCs fulfilling this role will enable future studies to better focus on mechanisms regulating T-cell homeostasis.

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Impact of multiple hits with cognate antigen on memory CD8+ T-cell fate

International Immunology ◽

10.1093/intimm/dxaa039 ◽

2020 ◽

Vol 32 (9) ◽

pp. 571-581 ◽

Cited By ~ 1

Author(s):

Shiki Takamura

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Memory T Cells ◽

Cd8 T Cell ◽

T Cell Subsets ◽

Primary Immune Response ◽

Memory T Cell ◽

Cognate Antigen ◽

Memory Cd8 T Cell

Abstract Antigen-driven activation of CD8+ T cells results in the development of a robust anti-pathogen response and ultimately leads to the establishment of long-lived memory T cells. During the primary response, CD8+ T cells interact multiple times with cognate antigen on distinct types of antigen-presenting cells. The timing, location and context of these antigen encounters significantly impact the differentiation programs initiated in the cells. Moderate re-activation in the periphery promotes the establishment of the tissue-resident memory T cells that serve as sentinels at the portal of pathogen entry. Under some circumstances, moderate re-activation of T cells in the periphery can result in the excessive expansion and accumulation of circulatory memory T cells, a process called memory inflation. In contrast, excessive re-activation stimuli generally impede conventional T-cell differentiation programs and can result in T-cell exhaustion. However, these conditions can also elicit a small population of exhausted T cells with a memory-like signature and self-renewal capability that are capable of responding to immunotherapy, and restoration of functional activity. Although it is clear that antigen re-encounter during the primary immune response has a significant impact on memory T-cell development, we still do not understand the molecular details that drive these fate decisions. Here, we review our understanding of how antigen encounters and re-activation events impact the array of memory CD8+ T-cell subsets subsequently generated. Identification of the molecular programs that drive memory T-cell generation will advance the development of new vaccine strategies that elicit high-quality CD8+ T-cell memory.

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

Journal of Experimental Medicine ◽

10.1084/jem.20161760 ◽

2017 ◽

Vol 214 (6) ◽

pp. 1593-1606 ◽

Cited By ~ 57

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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The lncRNA Snhg1-Vps13D vesicle trafficking system promotes memory CD8 T cell establishment via regulating the dual effects of IL-7 signaling

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00492-9 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Yanyan Zhang ◽

Baohua Li ◽

Qiang Bai ◽

Pengcheng Wang ◽

Gang Wei ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Expression Pattern ◽

Cd8 T Cells ◽

Vesicle Trafficking ◽

Cd8 T Cell ◽

T Cell Subsets ◽

Memory Cd8 T Cells ◽

Memory Cd8 T Cell

AbstractThe efficient induction and long-term persistence of pathogen-specific memory CD8 T cells are pivotal to rapidly curb the reinfection. Recent studies indicated that long-noncoding RNAs expression is highly cell- and stage-specific during T cell development and differentiation, suggesting their potential roles in T cell programs. However, the key lncRNAs playing crucial roles in memory CD8 T cell establishment remain to be clarified. Through CD8 T cell subsets profiling of lncRNAs, this study found a key lncRNA-Snhg1 with the conserved naivehi-effectorlo-memoryhi expression pattern in CD8 T cells of both mice and human, that can promote memory formation while impeding effector CD8 in acute viral infection. Further, Snhg1 was found interacting with the conserved vesicle trafficking protein Vps13D to promote IL-7Rα membrane location specifically. With the deep mechanism probing, the results show Snhg1-Vps13D regulated IL-7 signaling with its dual effects in memory CD8 generation, which not just because of the sustaining role of STAT5-BCL-2 axis for memory survival, but more through the STAT3-TCF1-Blimp1 axis for transcriptional launch program of memory differentiation. Moreover, we performed further study with finding a similar high-low-high expression pattern of human SNHG1/VPS13D/IL7R/TCF7 in CD8 T cell subsets from PBMC samples of the convalescent COVID-19 patients. The central role of Snhg1-Vps13D-IL-7R-TCF1 axis in memory CD8 establishment makes it a potential target for improving the vaccination effects to control the ongoing pandemic.

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T Cell–Independent Interleukin 15rα Signals Are Required for Bystander Proliferation

Journal of Experimental Medicine ◽

10.1084/jem.194.8.1187 ◽

2001 ◽

Vol 194 (8) ◽

pp. 1187-1194 ◽

Cited By ~ 131

Author(s):

James P. Lodolce ◽

Patrick R. Burkett ◽

David L. Boone ◽

Marcia Chien ◽

Averil Ma

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Bone Marrow Cells ◽

Cd8 T Cell ◽

Cell Receptor ◽

Poly I:C ◽

T Cell Homeostasis ◽

Memory Cd8 T Cells

Cytokine driven or “bystander” proliferation of T cells occurs in vivo independently of major histocompatibility complex–T cell receptor interactions. This process may be important for supporting T cell homeostasis and facilitating T cell responses to microbial antigens, and may involve the cytokine interleukin (IL)-15. In this study, we find that IL-15Rα–deficient (IL-15Rα−/−) mice fail to undergo poly I:C or IL-15 driven bystander proliferation of CD8+ T cells. Surprisingly, IL-15Rα−/− CD8+ T cells proliferate in response to poly I:C when adoptively transferred into normal mice, and normal CD8+ T cells fail to proliferate in IL-15Rα−/− mice. Normal mice reconstituted with IL-15Rα−/− bone marrow cells also fail to exhibit bystander responses. Thus, CD8+ T cell independent IL-15Rα signals from radiation sensitive hematopoietic cells are likely required for bystander responses. Moreover, normal CD8+ T cells proliferate in IL-15Rα−/− mice after treatment with IL-15. Therefore, IL-15Rα signals may mediate a positive feedback loop involving the further physiological production of IL-15. These findings provide new insights into how IL-15Rα supports memory phenotype CD8+ T cell proliferation, and suggest novel mechanisms by which memory CD8+ T cells are maintained in vivo.

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Sepsis leads to lasting changes in phenotype and function of memory CD8 T cells

eLife ◽

10.7554/elife.70989 ◽

2021 ◽

Vol 10 ◽

Author(s):

Isaac J jensen ◽

Xiang Li ◽

Patrick W McGonagill ◽

Qiang Shan ◽

Micaela G Fosdick ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cd8 T Cell ◽

Cell Phenotype ◽

Cytokine Storm ◽

Protective Function ◽

Memory Cd8 T Cells ◽

Memory Cd8 T Cell

The global health burden due to sepsis and the associated cytokine storm is substantial. While early intervention has improved survival during the cytokine storm, those that survive can enter a state of chronic immunoparalysis defined by transient lymphopenia and functional deficits of surviving cells. Memory CD8 T cells provide rapid cytolysis and cytokine production following re-encounter with their cognate antigen to promote long-term immunity, and CD8 T cell impairment due to sepsis can pre-dispose individuals to re-infection. While the acute influence of sepsis on memory CD8 T cells has been characterized, if and to what extent pre-existing memory CD8 T cells recover remains unknown. Here, we observed that central memory CD8 T cells (TCM) from septic patients proliferate more than those from healthy individuals. Utilizing LCMV immune mice and a CLP model to induce sepsis, we demonstrated that TCM proliferation is associated with numerical recovery of pathogen-specific memory CD8 T cells following sepsis-induced lymphopenia. This increased proliferation leads to changes in composition of memory CD8 T cell compartment and altered tissue localization. Further, memory CD8 T cells from sepsis survivors have an altered transcriptional profile and chromatin accessibility indicating long-lasting T cell intrinsic changes. The sepsis-induced changes in the composition of the memory CD8 T cell pool and transcriptional landscape culminated in altered T cell function and reduced capacity to control L. monocytogenes infection. Thus, sepsis leads to long-term alterations in memory CD8 T cell phenotype, protective function and localization potentially changing host capacity to respond to re-infection.

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Lineage-specific T-cell reconstitution following in vivo CD4+ and CD8+ lymphocyte depletion in nonhuman primates

Blood ◽

10.1182/blood-2010-01-263814 ◽

2010 ◽

Vol 116 (5) ◽

pp. 748-758 ◽

Cited By ~ 20

Author(s):

Jessica C. Engram ◽

Barbara Cervasi ◽

Jose A. M. Borghans ◽

Nichole R. Klatt ◽

Shari N. Gordon ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Cd8 T Cell ◽

Cd4 T Cell ◽

T Cell Homeostasis ◽

Cell Homeostasis ◽

Cell Repopulation

Abstract Many features of T-cell homeostasis in primates are still unclear, thus limiting our understanding of AIDS pathogenesis, in which T-cell homeostasis is lost. Here, we performed experiments of in vivo CD4+ or CD8+ lymphocyte depletion in 2 nonhuman primate species, rhesus macaques (RMs) and sooty mangabeys (SMs). Whereas RMs develop AIDS after infection with simian immunodeficiency virus (SIV), SIV-infected SMs are typically AIDS-resistant. We found that, in both species, most CD4+ or CD8+ T cells in blood and lymph nodes were depleted after treatment with their respective antibodies. These CD4+ and CD8+ lymphocyte depletions were followed by a largely lineage-specific CD4+ and CD8+ T-cell proliferation, involving mainly memory T cells, which correlated with interleukin-7 plasma levels. Interestingly, SMs showed a faster repopulation of naive CD4+ T cells than RMs. In addition, in both species CD8+ T-cell repopulation was faster than that of CD4+ T cells, with CD8+ T cells reconstituting a normal pool within 60 days and CD4+ T cells remaining below baseline levels up to day 180 after depletion. While this study revealed subtle differences in CD4+ T-cell repopulation in an AIDS-sensitive versus an AIDS-resistant species, such differences may have particular relevance in the presence of active SIV repli cation, where CD4+ T-cell destruction is chronic.

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Influenza- and MCMV-induced memory CD8 T cells control respiratory vaccinia virus infection despite residence in distinct anatomical niches

Mucosal Immunology ◽

10.1038/s41385-020-00373-4 ◽

2021 ◽

Author(s):

Suzanne P. M. Welten ◽

Josua Oderbolz ◽

Vural Yilmaz ◽

Susanna R. Bidgood ◽

Victoria Gould ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Vaccinia Virus ◽

Cd8 T Cells ◽

Cd8 T Cell ◽

T Cell Subsets ◽

Protective Capacity ◽

Peripheral Tissues ◽

Memory Cd8 T Cells ◽

Memory Cd8 T Cell

AbstractInduction of memory CD8 T cells residing in peripheral tissues is of interest for T cell-based vaccines as these cells are located at mucosal and barrier sites and can immediately exert effector functions, thus providing protection in case of local pathogen encounter. Different memory CD8 T cell subsets patrol peripheral tissues, but it is unclear which subset is superior in providing protection upon secondary infections. We used influenza virus to induce predominantly tissue resident memory T cells or cytomegalovirus to elicit a large pool of effector-like memory cells in the lungs and determined their early protective capacity and mechanism of reactivation. Both memory CD8 T cell pools have unique characteristics with respect to their phenotype, localization, and maintenance. However, these distinct features do not translate into different capacities to control a respiratory vaccinia virus challenge in an antigen-specific manner, although differential activation mechanisms are utilized. While influenza-induced memory CD8 T cells respond to antigen by local proliferation, MCMV-induced memory CD8 T cells relocate from the vasculature into the tissue in an antigen-independent and partially chemokine-driven manner. Together these results bear relevance for the development of vaccines aimed at eliciting a protective memory CD8 T cell pool at mucosal sites.

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Markers of memory CD8 T cells depicting the effect of the BNT162b2 mRNA COVID-19 vaccine in Japan

10.21203/rs.3.rs-936363/v1 ◽

2021 ◽

Author(s):

Hiroyuki Kondo ◽

Takahiro Kageyama ◽

Shigeru Tanaka ◽

Shin-ichi Tsukumo ◽

Kunihiro Otsuka ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Japanese Population ◽

Cd8 T Cell ◽

Memory Cd8 T Cells ◽

Effector Cells ◽

Cd8 Cells ◽

Memory Cd8 T Cell ◽

And Function

Abstract BNT162b2, a nucleoside-modified mRNA vaccine for SARS-CoV-2 spike glycoprotein (S), provides approximately 95% efficacy for preventing COVID-19. However, it remains unclear how effectively memory CD8+ T cells are generated and which genetic and environmental factors affect the generation and function of memory CD8+ T cells elicited by this vaccine. Here, we investigated the frequency and functions of memory CD8+ T cells 3 weeks after the second vaccination in the Japanese population. Using a peptide-MHC pentamer, we detected an increased number of memory CD8+ T cells in females compared with that in males, but the frequency of pentamer-positive cells was not correlated with antibody titers. Memory precursor effector cells (KLRG1-CD127+) among both CD8+ cells and pentamer+ cells and effector cells (CD38-HLA-DR+) among pentamer+ cells were more abundant in females than in males. Upon S protein-mediated stimulation of T cells, the intensity of CD107a and granzyme B expression was increased in females compared with that in males, indicating stronger memory CD8+ T cell responses in females than in males. Our studies showed that the BNT162b2 vaccine elicits increased memory CD8+ T cell proliferation and secondary CTL responses in females compared with those in males in the Japanese population. These findings provide an important basis for the distinct sex difference in cellular immune responses to mRNA vaccination and suggest that memory precursor effector cells can be a simple marker to evaluate and boost cellular immunity induced by BNT162b2.

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