Differential phenotypes of memory CD4 and CD8 T cells in the spleen and peripheral tissues following immunostimulatory therapy

Abstract In chronic HIV infection, virus-specific cytotoxic CD8 T cells showed expression of checkpoint receptors and impaired function. Therefore, restoration of CD8 T-cell function is critical in cure strategies. Here, we show that in vitro blockade of programmed cell death ligand 1 (PD-L1) by an anti-PD-L1 antibody (avelumab) in combination with recombinant human interleukin-15 (rhIL-15) synergistically enhanced cytokine secretion by proliferating HIVGag-specific CD8 T cells. In addition, these CD8 T cells have a CXCR3+PD1−/low phenotype, suggesting a potential to traffic into peripheral tissues. In vitro, proliferating CD8 T cells express PD-L1 suggesting that anti-PD-L1 treatment also targets virus-specific CD8 T cells. Together, these data indicate that rhIL-15/avelumab combination therapy could be a useful strategy to enhance CD8 T-cell function in cure strategies.

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Regulation of Cytokine Production by Virus-Specific CD8 T Cells in the Lungs

Journal of Virology ◽

10.1128/jvi.00840-08 ◽

2008 ◽

Vol 82 (16) ◽

pp. 7799-7811 ◽

Cited By ~ 24

Author(s):

Ross B. Fulton ◽

Matthew R. Olson ◽

Steven M. Varga

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Cytokine Production ◽

Memory T Cells ◽

Tissue Injury ◽

Ex Vivo ◽

Lung Parenchyma ◽

Host Cells ◽

Peripheral Tissues ◽

Specific Memory

ABSTRACT Inflammation and the elimination of infected host cells during an immune response often cause local tissue injury and immunopathology, which can disrupt the normal functions of tissues such as the lung. Here, we show that both virus-induced inflammation and the host tissue environment combine to influence the capacity of virus-specific CD4 and CD8 T cells to produce cytokines in various tissues. Decreased production of cytokines, such as IFN-γ and TNF-α, by antigen-specific T cells is more pronounced in peripheral tissues, such as the lung and kidney, than in secondary lymphoid organs, such as the spleen or lymph nodes. We also demonstrate that tissues regulate cytokine production by memory T cells independently of virus infection, as memory T cells that traffic into the lungs of naïve animals exhibit a reduced ability to produce cytokines following direct ex vivo peptide stimulation. Furthermore, we show that cytokine production by antigen-specific memory CD4 and CD8 T cells isolated from the lung parenchyma can be rescued by stimulation with exogenous peptide-pulsed antigen-presenting cells. Our results suggest that the regulation of T-cell cytokine production by peripheral tissues may serve as an important mechanism to prevent immunopathology and preserve normal tissue function.

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Major Histocompatibility Complex Class I–restricted Cross-presentation Is Biased towards High Dose Antigens and Those Released during Cellular Destruction

Journal of Experimental Medicine ◽

10.1084/jem.188.2.409 ◽

1998 ◽

Vol 188 (2) ◽

pp. 409-414 ◽

Cited By ~ 221

Author(s):

Christian Kurts ◽

Jacques F.A.P. Miller ◽

Rathan M. Subramaniam ◽

Francis R. Carbone ◽

William R. Heath

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

High Dose ◽

Tissue Destruction ◽

Peripheral Tissues ◽

Cross Presentation ◽

Histocompatibility Complex ◽

Presentation Pathway ◽

The Cross ◽

Cellular Destruction

Naive T cells recirculate mainly within the secondary lymphoid compartment, but once activated they can enter peripheral tissues and perform effector functions. To activate naive T cells, foreign antigens must traffic from the site of infection to the draining lymph nodes, where they can be presented by professional antigen presenting cells. For major histocompatibility complex class I–restricted presentation to CD8+ T cells, this can occur via the cross-presentation pathway. Here, we investigated the conditions allowing antigen access to this pathway. We show that the level of antigen expressed by peripheral tissues must be relatively high to facilitate cross-presentation to naive CD8+ T cells. Below this level, peripheral antigens did not stimulate by cross-presentation and were ignored by naive CD8+ T cells, although they could sensitize tissue cells for destruction by activated cytotoxic T lymphocytes (CTLs). Interestingly, CTL-mediated tissue destruction facilitated cross-presentation of low dose antigens for activation of naive CD8+ T cells. This represents the first in vivo evidence that cellular destruction can enhance access of exogenous antigens to the cross-presentation pathway. These data indicate that the cross-presentation pathway focuses on high dose antigens and those released during tissue destruction.

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Global Gene Expression of T Cells Is Differentially Regulated by Peritoneal Dendritic Cell Subsets in an IL-2 Dependent Manner

Frontiers in Immunology ◽

10.3389/fimmu.2021.648348 ◽

2021 ◽

Vol 12 ◽

Author(s):

Moah Sohn ◽

Hye Young Na ◽

Hyun Soo Shin ◽

Seul Hye Ryu ◽

Sejung Park ◽

...

Keyword(s):

Gene Expression ◽

T Cells ◽

Cd8 T Cells ◽

Global Gene Expression ◽

The Body ◽

Dependent Manner ◽

Soluble Factor ◽

Peripheral Tissues ◽

Unique Role ◽

Cell Responses

Dendritic cells (DCs) in peripheral tissues may have a unique role to regulate innate and adaptive immune responses to antigens that enter the tissues. Peritoneal cavity is the body compartment surrounding various tissues and organs and housing diverse immune cells. Here, we investigated the specialized features of classical DC (cDC) subsets following the intraperitoneal injection of a model antigen ovalbumin (OVA). Peritoneal cDC1s were superior to cDC2s in activating OVA-specific CD8 T cells, while both cDCs were similar in stimulating OVA-specific CD4 T cells. Each peritoneal cDC subset differentially regulated the homing properties of CD8 T cells. CD8 T cells stimulated by cDC1s displayed a higher level of lung-homing receptor CCR4, whereas those stimulated by cDC2s prominently expressed various homing receptors including gut-homing molecules CCR9 and α4β7. Also, we found that cDC1s played a dominating role over cDC2s in controlling the overall gene expression of CD8 T cells. Soluble factor(s) emanating from CD8 T cells stimulated by peritoneal cDC1s were responsible for mediating this dominance of cDC1s, and we identified IL-2 as a soluble factor regulating the global gene expression of T cells. Collectively, our study indicates that different peritoneal cDC subsets effectively diversify T cell responses by altering the level of cytokines, such as IL-2, in the milieu.

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CD28H expression identifies resident memory CD8 + T cells with less cytotoxicity in human peripheral tissues and cancers

OncoImmunology ◽

10.1080/2162402x.2018.1538440 ◽

2018 ◽

Vol 8 (2) ◽

pp. e1538440 ◽

Cited By ~ 3

Author(s):

Yu Tian ◽

Yi Sun ◽

Fan Gao ◽

Michelle R. Koenig ◽

Alexander Sunderland ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Peripheral Tissues ◽

Memory Cd8 T Cells

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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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CXCR6 by increasing retention of memory CD8+ T cells in the ovarian tumor microenvironment promotes immunosurveillance and control of ovarian cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-003329 ◽

2021 ◽

Vol 9 (10) ◽

pp. e003329

Author(s):

Ravikumar Muthuswamy ◽

AJ Robert McGray ◽

Sebastiano Battaglia ◽

Wenjun He ◽

Anthony Miliotto ◽

...

Keyword(s):

Ovarian Cancer ◽

T Cells ◽

Tumor Microenvironment ◽

Cd8 T Cells ◽

Ovarian Tumor ◽

Critical Role ◽

Peripheral Tissues ◽

Memory Cd8 T Cells ◽

Tumor Tissues ◽

And Control

PurposeResident memory CD8 T cells, owing to their ability to reside and persist in peripheral tissues, impart adaptive sentinel activity and amplify local immune response, and have beneficial implications for tumor surveillance and control. The current study aimed to clarify the less known chemotactic mechanisms that govern the localization, retention, and residency of memory CD8 T cells in the ovarian tumor microenvironment.Experimental designRNA and protein expressions of chemokine receptors in CD8+ resident memory T cells in human ovarian tumor-infiltrating CD8+ T cells and their association with survival were analyzed. The role of CXCR6 on antitumor T cells was investigated using prophylactic vaccine models in murine ovarian cancer.ResultsChemokine receptor profiling of CD8+CD103+ resident memory tumor-infiltrating lymphocytes in patients with ovarian cancer revealed high expression of CXCR6. Analysis of The Cancer Genome Atlas (TCGA) (ovarian cancer database revealed CXCR6 to be associated with CD103 and increased patient survival. Functional studies in mouse models of ovarian cancer revealed that CXCR6 is a marker of resident, but not circulatory, tumor-specific memory CD8+ T cells. CXCR6-deficient tumor-specific CD8+ T cells showed reduced retention in tumor tissues, leading to diminished resident memory responses and poor control of ovarian cancer.ConclusionsCXCR6, by promoting retention in tumor tissues, serves a critical role in resident memory T cell-mediated immunosurveillance and control of ovarian cancer. Future studies warrant exploiting CXCR6 to promote resident memory responses in cancers.

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