scholarly journals TGF-[beta]-dependent Lymphoid Tissue Residency of Stem-like T cells Limits the Response to Tumor Vaccine

2021 ◽  
Author(s):  
Guo Li ◽  
Liwen Wang ◽  
Chaoyu Ma ◽  
Wei Liao ◽  
Yong Liu ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Tumor Vaccine ◽  
Tumor Control ◽  
Lymphoid Tissues ◽  
Dependent Manner ◽  
Multiple Tumor ◽  
Draining Lymph Node ◽  
Resident Memory T Cells

Stem-like CD8+ T cells represent the key subset responding to multiple tumor immunotherapies, including tumor vaccination. However, the signals that control the differentiation of stem-like T cells are not entirely known. Most previous investigations on stem-like T cells are focused on tumor infiltrating T cells (TIL). The behavior of stem-like T cells in other tissues remains to be elucidated. Tissue-resident memory T cells (TRM) are often defined as a non-circulating T cell population residing in non-lymphoid tissues. TILs carrying TRM features are associated with better tumor control. Here, we found that stem-like CD8+ T cells differentiated into TRMs in a TGF-β and tumor antigen dependent manner almost exclusively in tumor draining lymph node (TDLN). TDLN-resident stem-like T cells were negatively associated with the response to tumor vaccine. In other words, after tumor vaccine, TDLN stem-like T cells transiently lost TRM features, differentiated into migratory effectors and exerted tumor control.

scholarly journals Route of Immunization with Peptide-pulsed Dendritic Cells Controls the Distribution of Memory and Effector T Cells in Lymphoid Tissues and Determines the Pattern of Regional Tumor Control

2003 ◽  
Vol 198 (7) ◽  
pp. 1023-1034 ◽  
Author(s):  
David W. Mullins ◽  
Stacey L. Sheasley ◽  
Rebecca M. Ream ◽  
Timothy N.J. Bullock ◽  
Yang-Xin Fu ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Lung Metastases ◽  
Memory Cell ◽  
Lung Tumors ◽  
Tumor Control ◽  
Lymphoid Tissues ◽  
Memory Cd8 T Cells ◽  
And Control

We have established that the route of immunization with peptide-pulsed, activated DC leads to memory CD8+ T cells with distinct distributions in lymphoid tissues, which determines the ability to control tumors growing in different body sites. Both intravenous (i.v.) and subcutaneous (s.c.) immunization induced memory T cells in spleen and control of metastatic-like lung tumors. s.c. immunization also induced memory T cells in lymph nodes (LNs), imparting protection against subcutaneously growing tumors. In contrast, i.v. immunization-induced memory was restricted to spleen and failed to impart protective immunity against subcutaneously growing tumors. Memory cell distribution and tumor control were both linked to injection route–dependent localization of DCs in lymphoid compartments. Using peripheral LN–ablated mice, these LNs were shown to be essential for control of subcutaneously growing tumors but not lung metastases; in contrast, using immunized asplenic mice, we found that the spleen is necessary and sufficient for control of lung tumors, but unnecessary for control of subcutaneously growing tumors. These data demonstrate the existence of a previously undescribed population of splenic-resident memory CD8 T cells that are essential for the control of lung metastases. Thus, regional immunity based on memory T cell residence patterns is an important factor in DC-based tumor immunotherapy.

scholarly journals CXCR6 regulates localization of tissue-resident memory CD8 T cells to the airways

2019 ◽  
Vol 216 (12) ◽  
pp. 2748-2762 ◽  
Author(s):  
Alexander N. Wein ◽  
Sean R. McMaster ◽  
Shiki Takamura ◽  
Paul R. Dunbar ◽  
Emily K. Cartwright ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Protective Immunity ◽  
Memory T Cells ◽  
Respiratory Pathogens ◽  
First Line ◽  
Memory Cd8 T Cells ◽  
Effector Functions ◽  
Signaling Axis ◽  
Resident Memory T Cells

Resident memory T cells (TRM cells) are an important first-line defense against respiratory pathogens, but the unique contributions of lung TRM cell populations to protective immunity and the factors that govern their localization to different compartments of the lung are not well understood. Here, we show that airway and interstitial TRM cells have distinct effector functions and that CXCR6 controls the partitioning of TRM cells within the lung by recruiting CD8 TRM cells to the airways. The absence of CXCR6 significantly decreases airway CD8 TRM cells due to altered trafficking of CXCR6−/− cells within the lung, and not decreased survival in the airways. CXCL16, the ligand for CXCR6, is localized primarily at the respiratory epithelium, and mice lacking CXCL16 also had decreased CD8 TRM cells in the airways. Finally, blocking CXCL16 inhibited the steady-state maintenance of airway TRM cells. Thus, the CXCR6/CXCL16 signaling axis controls the localization of TRM cells to different compartments of the lung and maintains airway TRM cells.

Circulating memory CD8 + T cells are limited in forming CD103 + tissue‐resident memory T cells at mucosal sites after reinfection

2020 ◽  
Author(s):  
Felix M. Behr ◽  
Ammarina Beumer‐Chuwonpad ◽  
Natasja A. M. Kragten ◽  
Thomas H. Wesselink ◽  
Regina Stark ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Memory Cd8 T Cells ◽  
Resident Memory T Cells

scholarly journals CXCR6 governs the retention of tissue-resident memory T cells to promote enhanced surveillance and control of ovarian cancer

2020 ◽  
Author(s):  
Ravikumar Muthuswamy ◽  
AJ Robert McGray ◽  
Sebastiano Battaglia ◽  
Wenjun He ◽  
Anthony Miliotto ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Ovarian Tumor ◽  
Memory T Cells ◽  
Memory Cell ◽  
Tumor Control ◽  
Control Analysis ◽  
Resident Memory T Cells ◽  
And Control

AbstractWhile the beneficial role played by tissue-resident memory T cells (Trm) in tumor control has emerged, the chemotactic mechanisms associated with their localization and retention in the tumor microenvironment (TME) of cancers including ovarian are poorly understood. The current study has identified chemokine receptor CXCR6 as crucial for Trm responses to ovarian cancer by promoting their localization and retention in the ovarian tumor microenvironment. In human ovarian cancer patients, CXCR6 significantly marked CD8+ CD103+ tumor-infiltrating Trm cells. Functional studies in mice revealed high expression of CXCR6 in tumor-specific T cells that reside in tissues, but not by those in circulation. Knockout of CXCR6 in tumor-specific T cells led to a heightened circulatory response in blood, but diminished resident memory cell accumulation in tumors, culminating in poor tumor control. Analysis of Wild type (Wt.) and CXCR6KO (KO) tumor-specific T cells trafficking in recipient mice using bioluminescent imaging revealed that compared to Wt., KO T cells preferentially localized to the spleen, indicating the possibility of reduced retention in tumor tissues. These findings indicate that CXCR6 by mediating increased retention of tumor-specific T cells in the ovarian tumor microenvironment, promotes resident memory T cell-mediated surveillance and control of ovarian cancer.

Skin-resident memory CD8+ T cells trigger a state of tissue-wide pathogen alert

Science ◽  
2014 ◽  
Vol 346 (6205) ◽  
pp. 101-105 ◽  
Author(s):  
Silvia Ariotti ◽  
Marc A. Hogenbirk ◽  
Feline E. Dijkgraaf ◽  
Lindy L. Visser ◽  
Mirjam E. Hoekstra ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Mouse Skin ◽  
Memory Cd8 T Cells ◽  
Vaccination Strategies ◽  
Rapid Control ◽  
Pathogen Entry ◽  
Specific Tissue ◽  
Resident Memory T Cells

After an infection, pathogen-specific tissue-resident memory T cells (TRM cells) persist in nonlymphoid tissues to provide rapid control upon reinfection, and vaccination strategies that create TRM cell pools at sites of pathogen entry are therefore attractive. However, it is not well understood how TRM cells provide such pathogen protection. Here, we demonstrate that activated TRM cells in mouse skin profoundly alter the local tissue environment by inducing a number of broadly active antiviral and antibacterial genes. This “pathogen alert” allows skin TRM cells to protect against an antigenically unrelated virus. These data describe a mechanism by which tissue-resident memory CD8+ T cells protect previously infected sites that is rapid, amplifies the activation of a small number of cells into an organ-wide response, and has the capacity to control escape variants.

scholarly journals Retrograde migration supplies resident memory T cells to lung-draining LN after influenza infection

2020 ◽  
Vol 217 (8) ◽  
Author(s):  
J. Michael Stolley ◽  
Timothy S. Johnston ◽  
Andrew G. Soerens ◽  
Lalit K. Beura ◽  
Pamela C. Rosato ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Influenza Infection ◽  
Granzyme B ◽  
Lymphatic Vessels ◽  
Cd8 T Cell ◽  
Lung Infection ◽  
Cell Responses ◽  
Resident Memory T Cells

Numerous observations indicate that resident memory T cells (TRM) undergo unusually rapid attrition within the lung. Here we demonstrate that contraction of lung CD8+ T cell responses after influenza infection is contemporized with egress of CD69+/CD103+ CD8+ T cells to the draining mediastinal LN via the lymphatic vessels, which we term retrograde migration. Cells within the draining LN retained canonical markers of lung TRM, including CD103 and CD69, lacked Ly6C expression (also a feature of lung TRM), maintained granzyme B expression, and did not equilibrate among immunized parabiotic mice. Investigations of bystander infection or removal of the TCR from established memory cells revealed that the induction of the TRM phenotype was dependent on antigen recognition; however, maintenance was independent. Thus, local lung infection induces CD8+ T cells with a TRM phenotype that nevertheless undergo retrograde migration, yet remain durably committed to the residency program within the draining LN, where they provide longer-lived regional memory while chronicling previous upstream antigen experiences.

scholarly journals CD4+ resident memory T cells dominate immunosurveillance and orchestrate local recall responses

2019 ◽  
Vol 216 (5) ◽  
pp. 1214-1229 ◽  
Author(s):  
Lalit K. Beura ◽  
Nancy J. Fares-Frederickson ◽  
Elizabeth M. Steinert ◽  
Milcah C. Scott ◽  
Emily A. Thompson ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Immune Cell ◽  
Memory T Cells ◽  
Cell Immunity ◽  
And Migration ◽  
Resident Memory T Cells ◽  
Memory Cd4 T Cells

This study examines the extent to which memory CD4+ T cells share immunosurveillance strategies with CD8+ resident memory T cells (TRM). After acute viral infection, memory CD4+ T cells predominantly used residence to survey nonlymphoid tissues, albeit not as stringently as observed for CD8+ T cells. In contrast, memory CD4+ T cells were more likely to be resident within lymphoid organs than CD8+ T cells. Migration properties of memory-phenotype CD4+ T cells in non-SPF parabionts were similar, generalizing these results to diverse infections and conditions. CD4+ and CD8+ TRM shared overlapping transcriptional signatures and location-specific features, such as granzyme B expression in the small intestine, revealing tissue-specific and migration property–specific, in addition to lineage-specific, differentiation programs. Functionally, mucosal CD4+ TRM reactivation locally triggered both chemokine expression and broad immune cell activation. Thus, residence provides a dominant mechanism for regionalizing CD4+ T cell immunity, and location enforces shared transcriptional, phenotypic, and functional properties with CD8+ T cells.

scholarly journals Resident Memory T Cells and Their Effect on Cancer

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 562
Author(s):  
Daniel J. Craig ◽  
Justin F. Creeden ◽  
Katelyn R. Einloth ◽  
Cassidy E. Gillman ◽  
Laura Stanbery ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Cell Transformation ◽  
Cell Phenotype ◽  
Long Term Memory ◽  
Potential Applications ◽  
Resident Memory T Cells ◽  
Cancer Immunosurveillance

Resident memory T (TRM) cells are a unique subset of CD8+ T cells that are present within certain tissues and do not recirculate through the blood. Long term memory establishment and maintenance are dependent on tissue population of memory T cells. They are characterized by dual CD69/CD103 positivity, and play a role in both response to viral infection and local cancer immunosurveillance. Human TRM cells demonstrate the increased expression of adhesion molecules to facilitate tissue retention, have reduced proliferation and produce both regulatory and immune responsive cytokines. TRM cell phenotype is often characterized by a distinct expression profile driven by Runx3, Blimp1, and Hobit transcription factors. The accumulation of TRM cells in tumors is associated with increased survival and response to immunotherapies, including anti-PD-1 and anti-CTLA-4. In this review, we explore potential mechanisms of TRM cell transformation and maintenance, as well as potential applications for the use of TRM cells in both the development of supportive therapies and establishing more accurate prognoses.

scholarly journals The relationship between CD4+ follicular helper T cells and CD8+ resident memory T cells: sisters or distant cousins?

2020 ◽  
Vol 32 (9) ◽  
pp. 583-587 ◽  
Author(s):  
Changwei Peng ◽  
Stephen C Jameson
Keyword(s):  
T Cells ◽  
Immune System ◽  
Protective Immunity ◽  
Memory T Cells ◽  
Helper T Cells ◽  
Lymphoid Tissues ◽  
Follicular Helper T Cells ◽  
Follicular Helper ◽  
Resident Memory T Cells ◽  
The Relationship

Abstract Independent studies over the last decade have characterized the properties of non-circulating CD8+ ‘resident’ memory T cells (TRM), which offer barrier protective immunity in non-lymphoid tissues and CD4+ follicular helper T cells (TFH), which mediate B-cell help in lymphoid sites. Despite their very different biological roles in the immune system, intriguing parallels have been noted between the trafficking properties and differentiation cues of these populations, parallels which have only sharpened with recent findings. In this review, we explore the features that underlie these similarities and discuss whether these indicate meaningful homologies in the development of CD8+ TRM and CD4+ TFH or reflect resemblances which are only ‘skin-deep’.

scholarly journals Tissue-resident CD8+ T cells drive age-associated chronic lung sequelae following viral pneumonia

2020 ◽  
Author(s):  
Nick P. Goplen ◽  
Yue Wu ◽  
Youngmin Son ◽  
Chaofan Li ◽  
Zheng Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Protective Immunity ◽  
Viral Infections ◽  
Memory T Cells ◽  
Viral Pneumonia ◽  
Lung Pathology ◽  
Tcr Signaling ◽  
Respiratory Viral Infections ◽  
Resident Memory T Cells

AbstractLower respiratory viral infections, such as influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infections, often cause severe viral pneumonia in aged individuals. Here, we report that influenza viral pneumonia leads to chronic non-resolving lung pathology and exaggerated accumulation of CD8+ tissue-resident memory T cells (TRM) in the respiratory tract of aged hosts. TRM accumulation relies on elevated TGF-β present in aged tissues. Further, we show that TRM isolated from aged lungs lack a subpopulation characterized by expression of molecules involved in TCR signaling and effector function. Consequently, TRM cells from aged lungs were insufficient to provide heterologous protective immunity. Strikingly, the depletion of CD8+ TRM cells dampens persistent chronic lung inflammation and ameliorates tissue fibrosis in aged, but not young, animals. Collectively, our data demonstrate that age-associated TRM cell malfunction supports chronic lung inflammatory and fibrotic sequelae following viral pneumonia in aged hosts.

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