scholarly journals Endometrial Cancer Suppresses CD8+ T Cell-Mediated Cytotoxicity in Postmenopausal Women

2021 ◽  
Vol 12 ◽  
Author(s):  
Mickey V. Patel ◽  
Zheng Shen ◽  
Marta Rodriguez-Garcia ◽  
Edward J. Usherwood ◽  
Laura J. Tafe ◽  
...  
Keyword(s):  
T Cells ◽  
Endometrial Cancer ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Cd8 T Cells ◽  
Gynecological Cancer ◽  
Cd8 T Cell ◽  
Target Cells ◽  
Tumor Environment ◽  
Immunosuppressive Cytokines

Endometrial cancer is the most common gynecological cancer. To investigate how it suppresses host immune function, we isolated CD8+ T cells from endometrial endometroid carcinomas and adjacent non-cancerous endometrium and determined if the tumor environment regulates cytotoxic capacity. Endometrial carcinomas had increased numbers of CD8+ T cells compared to adjacent non-cancerous endometrium. Tumor CD8+ T cells expressed significantly less granzyme A (GZA), B (GZB), and PD-1 than those in adjacent non-cancerous tissues and also had significantly lower cytotoxic killing of allogeneic target cells. CD103-CD8+ T cells, but not CD103+CD8+ T cells, from both adjacent and tumor tissue were primarily responsible for killing of allogeneic target cells. Secretions recovered from endometrial carcinoma tissues suppressed CD8+ cytotoxic killing and lowered perforin, GZB and PD-1 expression relative to non-tumor CD8+ T cells. Furthermore, tumor secretions contained significantly higher levels of immunosuppressive cytokines including TGFβ than non-tumor tissues. Thus, the tumor microenvironment suppresses cytotoxic killing by CD8+ T cells via the secretion of immunosuppressive cytokines leading to decreased expression of intracellular cytolytic molecules. These studies demonstrate the complexity of CD8+ T cell regulation within the endometrial tumor microenvironment and provide a foundation of information essential for the development of therapeutic strategies for gynecological cancers.

scholarly journals Generation of Human CD8 T Regulatory Cells by CD40 Ligand–activated Plasmacytoid Dendritic Cells

2002 ◽  
Vol 195 (6) ◽  
pp. 695-704 ◽  
Author(s):  
Michel Gilliet ◽  
Yong-Jun Liu
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Transforming Growth Factor ◽  
Cd8 T Cell ◽  
Cd40 Ligand ◽  
Plasmacytoid Dendritic Cells ◽  
Target Cells ◽  
Ifn Γ

Although CD8 T cell–mediated immunosuppression has been a well-known phenomenon during the last three decades, the nature of primary CD8 T suppressor cells and the mechanism underlying their generation remain enigmatic. We demonstrated that naive CD8 T cells primed with allogeneic CD40 ligand–activated plasmacytoid dendritic cells (DC)2 differentiated into CD8 T cells that displayed poor secondary proliferative and cytolytic responses. By contrast, naive CD8 T cells primed with allogeneic CD40 ligand–activated monocyte-derived DCs (DC1) differentiated into CD8 T cells, which proliferated to secondary stimulation and killed allogeneic target cells. Unlike DC1-primed CD8 T cells that produced large amounts of interferon (IFN)-γ upon restimulation, DC2-primed CD8 T cells produced significant amounts of interleukin (IL)-10, low IFN-γ, and no IL-4, IL-5, nor transforming growth factor (TGF)-β. The addition of anti–IL-10–neutralizing monoclonal antibodies during DC2 and CD8 T cell coculture, completely blocked the generation of IL-10–producing anergic CD8 T cells. IL-10–producing CD8 T cells strongly inhibit the allospecific proliferation of naive CD8 T cells to monocytes, and mature and immature DCs. This inhibition was mediated by IL-10, but not by TGF-β. IL-10–producing CD8 T cells could inhibit the bystander proliferation of naive CD8 T cells, provided that they were restimulated nearby to produce IL-10. IL-10–producing CD8 T cells could not inhibit the proliferation of DC1-preactivated effector T cells. This study demonstrates that IL-10–producing CD8 T cells are regulatory T cells, which provides a cellular basis for the phenomenon of CD8 T cell–mediated immunosuppression and suggests a role for plasmacytoid DC2 in immunological tolerance.

AAV-2 Capsid-Specific CD8+ T Cells Limit the Duration of Gene Therapy in Humans and Cross-React with AAV-8 Capsid.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 455-455 ◽  
Author(s):  
Federico Mingozzi ◽  
Marcela V. Maus ◽  
Denise E. Sabatino ◽  
Daniel J. Hui ◽  
John E.J. Rasko ◽  
...  
Keyword(s):  
Gene Therapy ◽  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Transgene Expression ◽  
Cd8 T Cell ◽  
Target Cells

Abstract Efforts to establish an adeno-associated viral (AAV) vector-mediated gene therapy for the treatment of hemophilia B have been hindered by an immune response to the viral capsid antigen. Preclinical studies in small and large animal models of the disease showed long-term factor IX (F.IX) transgene expression and correction of the phenotype. However, in a recent phase I/II clinical trial in humans (Manno et al., Nat. Med. 2006), after hepatic gene transfer with an AAV-2 vector expressing human F.IX transgene, expression lasted for only a few weeks, declining to baseline concurrently with a peak in liver enzymes. We hypothesized that T cells directed towards AAV capsid antigens displayed by transduced hepatocytes were activated and these mediated destruction of the transduced hepatocytes, thereby causing loss of transgene expression and a transient transaminitis. Peripheral blood mononuclear cells isolated from AAV-infused subjects were stained with an AAV capsid-specific MHC class I pentamer either directly or after in vitro expansion. Two weeks after vector infusion 0.14% of circulating CD8+ T cells were capsid-specific on direct staining, and five weeks after infusion the capsid-specific population had expanded to 0.5% of the circulating CD8+ T cells, indicating proliferation of this T cell subset. By 20 weeks after vector infusion, the capsid-specific CD8+ T cell population had contracted to the level seen at 2 weeks. The expansion and contraction of this capsid-specific CD8+ T cell population paralleled the rise and fall of serum transaminases in the subject observed. Subsequent ex vivo studies of PBMC showed the presence of a readily expandable pool of capsid-specific CD8+ T cells up to 2.5 years post vector-infusion. Similarly, we were able to expand AAV-specific CD8+ T cells from peripheral blood of normal donors, suggesting the existence of a T cell memory pool. Expanded CD8+ T cells were functional as evidenced by specific lysis of HLA-matched target cells and by IFN-γsecretion in response to AAV epitopes. It has been argued that potentially harmful immune responses could be avoided by switching AAV serotypes, however, capsid protein sequences are highly conserved among different serotypes, as are some immunodominant epitopes that we identified. Indeed, we demonstrated that capsid-specific CD8+ T cells from AAV-infused hemophilic subjects functionally cross-react with AAV-8. Moreover, cells expanded from normal donors with AAV-2 vector capsids proliferated upon culture with AAV-8 capsids, demonstrating that both vectors could be processed appropriately in vitro to present the epitopic peptide to capsid-specific T cells. This suggests that AAV-2-specific memory CD8+ T cells normally present in humans likely would expand upon exposure to AAV-8 capsid epitopes. We conclude that the use of immunomodulatory therapy may be a better approach to achieving durable transgene expression in the setting of AAV-mediated gene therapy.

Latent-Membrane 2a Specific CTL’s but Not Latent-Mebrane 1 Specific CTL’s Lysis Efficiently Hodgkin Lymphoma Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4991-4991
Author(s):  
Max S. Topp ◽  
Jan Diekamm ◽  
Olaf Beck ◽  
Georg Rauser ◽  
Kai Hauschulz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Adoptive Immunotherapy ◽  
Cytokine Production ◽  
Cd8 T Cell ◽  
Rapid Expansion ◽  
Target Cells ◽  
Specific Lysis ◽  
Healthy Donors

Abstract Relapse is the leading cause of treatment failure after allogeneic SCT of Hodgkin Disease (HD). As Ebstein-Barr infection (EBV) is associated with 60% of all HD cases, adoptive immunotherapy with donor derived EBV-specific T-cells lines has resulted in disease control of allogeneic SCT. Potential targets for the adoptively transferred T-cells are the type II latency protein LMP-1 and LMP-2a, which are both homogenously expressed by HD cells. In healthy individuals, both LMP-1 and LMP-2a elicits subdominant CD8+ T-cell responses with frequencies of less than 1:10000. LMP-1 and LMP-2a specific T-cells from 1x108 PBMC derived from HLA A*0201+healthy donors were stimulated with the HLA A*0201 LMP1-epitopes YLLEMLWRL and YLGQNWWTL and the HLA A*0201 LMP-2a epitope CLGGLLTM. Activated T-cells were selected by the cytokine secretion assay and expanded for 10 days. In 85% of donors 1.7 x106 (range 0.7 –4.5 x106; n=13) LMP-1 or LMP-2a specific CD8+ T-cell could be generated with an average purity of 83% as determined by tetramer staining. LMP1- and LMP2a-specific CD8+ T-cells were then expanded 3000 x in 14 d by the rapid expansion protocol and evaluated functionally for cytokine production and specific lysis. Both LMP-1 and LMP-2a specific CD8+ T-cells retained specific cytokine production if stimulated with peptide pulsed targets, efficiently lysed peptid pulsed targets. Surprisingly, if LMP-1 was presented endogenously by EBV positive targets or by targets cells transduced with LMP-1, no cytokine production or specific lysis was detected despite protein expression of LMP-1 in all targets. In contrast, IFN-γ production could be readily detected in LMP-2a-specific CD8+ T-cells after stimulation with target cells processing endogenously the LMP-2a antigen as well as specific lysis of EBV positive target cells. Furthermore, LMP2a specific CD8+ demostrated also specific lyse of Hodgkin-cells expressing the LMP2a (30:1 E/T ratio; 29,3%) where as LMP-1-specific CD8+ T-cells could not lyse HD-cells. In summary, LMP-1 and LMP-2a specific T-cells, although present at undectable levels in healthy donors, can be readily selected and expanded to up to 6x109 antigen-specific T-cells in less than 4 weeks starting from 1x108 PBMC. Based on this data, adoptive immunotherapy of relapsed EBV positive HD after allogeneic SCT should be preferentially performed with LMP-2a specific CD8+ T-cells rather than with LMP-1 specific CD8+ T-cells.

Perforin and Fas Ligand Are Required for the Regulation of Alloreactive CD8+ T Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3052-3052
Author(s):  
Yoshinobu Maeda ◽  
Robert B. Levy ◽  
Pavan Reddy ◽  
Chen Liu ◽  
Takanori Teshima ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Fas Ligand ◽  
Serum Levels ◽  
Cd8 T Cell ◽  
Rapid Decline ◽  
Target Cells ◽  
Donor T Cells

Abstract We evaluated the role of Fas ligand and perforin, the major T cell-mediated cytotoxic pathways that regulate T cell homeostasis, in a CD8+ T cell mediated model of graft-versus-host disease (GVHD) where donor and recipients differ at a single MHC class I antigen (B6 → bm1). Lethally irradiated (11Gy) bm1 mice were transplanted with T cell depleted BM and CD8+ T cells from either wild type (wt) or cytotoxic double deficient (cdd, deficient in both pathways) B6 donors. We hypothesized that cdd CD8+ T cells would be unable to mediate significant GVHD. Contrary to our hypothesis, recipients of cdd donor CD8+ T cells demonstrated significantly greater histopathologic damage from GVHD and increased serum levels of IFN-gamma and TNF-alpha compared to controls (Table 1). In order to understand this increase, we evaluated the in vivo expansion of donor T cells in these recipients as well as in BMT recipients of allogeneic CD8+ T cells from FasL deficient (gld) and perforin deficient (pfp−/−) donors. CD8+ wt T cells expanded until at day 10 after BMT, followed by a rapid decline. By contrast, cdd CD8+ T cells expanded continuously up to day 30 after BMT, peaking at almost one hundred times the number of wt T cells. gld T cells showed kinetics similar to wt T cells, whereas the pfp−/− T cells showed a significantly greater peak on day 10 but a similar contraction by day 30. Percentages of annexin+ cdd donor CD8+ T cells were significantly reduced compared to the other groups. Persistence of host antigen presenting cells did not account for the unrestrained expansion of cdd donor T cells because host dendritic cells were not detected in either the spleen, BM or gut of recipients of cdd CD8+ T cells on day 6 after BMT. In addition, alloantigen expression on epithelial target cells did not enhance GVHD because B6 donor cdd T cells induced equivalently lethal GVHD in [bm1 → B6] and [bm1 → bm1] chimeras (MST of 30 days and 27 days, respectively). We conclude that both perforin and Fas ligand pathways are required for alloreactive CD8+ T cell populations to contract after their initial expansion during a GVH reaction and that the absence of both these pathways results in donor CD8+ T cell unrestricted expansion and more severe GVHD. Table 1 GVHD score (gut) IFN-g (pg/ml) TNF-a (pg/ml) CD8+T cell (x10e6) Annexin+CD8+(%) cdd vs. wt, *P<0.05 Wt 4.0±0.4 110±12 6.5±2.7 0.9±0.2 81±3.3 Cdd 5.7±0.3* 263±71* 64.6±3.2* 80.1±4.0* 62±3.6* Pfp−/− ND ND ND 2.6±0.7 73±5.1 Gld ND ND ND 1.7±0.4 80±0.6

scholarly journals Estimating In Vivo Death Rates of Targets due to CD8 T-Cell-Mediated Killing

2008 ◽  
Vol 82 (23) ◽  
pp. 11749-11757 ◽  
Author(s):  
Vitaly V. Ganusov ◽  
Rob J. De Boer
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Bacterial Infections ◽  
Cytotoxic T Lymphocyte ◽  
Cd8 T Cell ◽  
Target Cells ◽  
Published Data ◽  
Memory Cd8 T Cells

ABSTRACT Despite recent advances in immunology, several key parameters determining virus dynamics in infected hosts remain largely unknown. For example, the rate at which specific effector and memory CD8 T cells clear virus-infected cells in vivo is hardly known for any viral infection. We propose a framework to quantify T-cell-mediated killing of infected or peptide-pulsed target cells using the widely used in vivo cytotoxicity assay. We have reanalyzed recently published data on killing of peptide-pulsed splenocytes by cytotoxic T lymphocytes and memory CD8 T cells specific to NP396 and GP276 epitopes of lymphocytic choriomeningitis virus (LCMV) in the mouse spleen. Because there are so many effector CD8 T cells in spleens of mice at the peak of the immune response, NP396- and GP276-pulsed targets are estimated to have very short half-lives of 2 and 14 min, respectively. After the effector numbers have diminished, i.e., in LCMV-immune mice, the half-lives become 48 min and 2.8 h for NP396- and GP276-expressing targets, respectively. Analysis of several alternative models demonstrates that the estimates of half-life times of peptide-pulsed targets are not affected when changes are made in the model assumptions. Our report provides a unifying framework to compare killing efficacies of CD8 T-cell responses specific to different viral and bacterial infections in vivo, which may be used to compare efficacies of various cytotoxic-T-lymphocyte-based vaccines.

Anti-Tumor TCF1+ CD8 T Cells are Functionally Diverse and Evolve During Tumorigenesis and Progression

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S5-S6
Author(s):  
Jason Schenkel ◽  
Rebecca Herbst ◽  
David Canner ◽  
Amy Li ◽  
Michelle Hillman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Early Stage ◽  
Cd8 T Cell ◽  
Temporal Analysis ◽  
T Cell Response ◽  
Target Cells ◽  
Early Stage Disease ◽  
Longitudinal Response

Abstract CD8+ T cells drive protective responses against infection and cancer. In the context of chronic antigen stimulation, CD8+ T cells become progressively dysfunctional, losing the ability to proliferate, secrete cytokines, and kill target cells. While dysfunctional CD8 T cells have been characterized in infection, studies examining longitudinal responses in tumors have been limited. Here, in an autochthonous model of lung adenocarcinoma using high dimensional flow cytometry and single cell RNA sequencing, we demonstrate that tumor specific CD8 T cell heterogeneity is dynamic, revealing multiple dysfunctional-like CD8 T cell populations. Among these states, we identify TCF-1+ CD8 T cells, a population previously associated with superior functionality. Temporal analysis revealed heterogeneity within the TCF-1+ CD8+ T cell compartment - SlamF6+ CD8 T cells were predominant in early stage disease, while SlamF6- CD8 T cells appeared later and were the majority during progression. Functionally, the SlamF6+ population was proliferative and expressed more inhibitory receptors than SlamF6- cells. However, SlamF6+ CD8 T cells gradually lost the ability to divide and secrete cytokines over the course of tumorigenesis, demonstrating that they become dysfunctional over time. Collectively, our results provide new insights into longitudinal response of TCF-1+ T cells over the course of tumorigenesis and have therapeutic implications for modulating the anti-tumor T cell response.

scholarly journals CD8+ T cell epitope variations suggest a potential antigen presentation deficiency for spike protein of SARS-CoV-2

2021 ◽  
Author(s):  
Congling Qiu ◽  
Chanchan Xiao ◽  
Zhigang Wang ◽  
Xiongfei Chen ◽  
Lijuan Gao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Vaccine Development ◽  
Cell Epitope ◽  
Cd8 T Cell ◽  
Spike Protein ◽  
Target Cells

AbstractCOVID-19 is caused by a newly identified coronavirus, SARS-CoV-2, and has become a pandemic around the world. The illustration of the immune responses against SARS-CoV-2 is urgently needed for understanding the pathogenesis of the disease and its vaccine development. CD8+ T cells are critical for virus clearance and induce long lasting protection in the host. Here we identified specific HLA-A2 restricted T cell epitopes in the spike protein of SARS-CoV-2. Seven epitope peptides (n-Sp1, 2, 6, 7, 11, 13, 14) were confirmed to bind with HLA-A2 and potentially be presented by antigen presenting cells to induce host immune responses. Tetramers containing these peptides could interact with specific CD8+ T cells from convalescent COVID-19 patients, and one dominant epitope (n-Sp1) was defined. In addition, these epitopes could activate and generate epitope-specific T cells in vitro, and those activated T cells showed cytotoxicity to target cells. Meanwhile, all these epitopes exhibited high frequency of variations. Among them, n-Sp1 epitope variation 5L>F significantly decreased the proportion of specific T cell activation; n-Sp1 epitope 8L>V variant showed significantly reduced binding to HLA-A2 and decreased the proportion of n-Sp1-specific CD8+ T cell, which potentially contributes to the immune escape of SAR-CoV-2.

scholarly journals Senescent Tumor CD8+ T Cells: Mechanisms of Induction and Challenges to Immunotherapy

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2828
Author(s):  
Wei Liu ◽  
Paweł Stachura ◽  
Haifeng C. Xu ◽  
Sanil Bhatia ◽  
Arndt Borkhardt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cell Senescence ◽  
Cellular Processes ◽  
State Present ◽  
T Cell Senescence

The inability of tumor-infiltrating T lymphocytes to eradicate tumor cells within the tumor microenvironment (TME) is a major obstacle to successful immunotherapeutic treatments. Understanding the immunosuppressive mechanisms within the TME is paramount to overcoming these obstacles. T cell senescence is a critical dysfunctional state present in the TME that differs from T cell exhaustion currently targeted by many immunotherapies. This review focuses on the physiological, molecular, metabolic and cellular processes that drive CD8+ T cell senescence. Evidence showing that senescent T cells hinder immunotherapies is discussed, as are therapeutic options to reverse T cell senescence.

scholarly journals Breast Tumor Microenvironment in Black Women: A Distinct Signature of CD8+ T Cell Exhaustion

2021 ◽  
Author(s):  
Song Yao ◽  
Ting-Yuan David Cheng ◽  
Ahmed Elkhanany ◽  
Li Yan ◽  
Angela Omilian ◽  
...  
Keyword(s):  
T Cells ◽  
Black Women ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Racial Differences ◽  
Cd8 T Cells ◽  
Tumor Biology ◽  
Cd8 T Cell ◽  
Health Study ◽  
Immune Phenotypes

Abstract Background Blacks tend to have a stronger inflammatory immune response than Whites. We hypothesized that racial differences in host immunity also manifest in the tumor microenvironment (TME), constituting part of a distinct aggressive tumor biology underlying higher mortality in Black women. Methods Pathological and gene expression profiling approaches were used for characterizing infiltrating immune cells in breast TME from 1,315 patients from the Women’s Circle of Health Study. Racial differences in tumor immune phenotypes were compared, with results validated in a publicly accessible dataset. Prognostic associations of immune phenotypes were assessed in three independent cohorts. Results We found marked and consistent differences in tumor immune responses between Black and White patients. Not only did tumors from Blacks display a stronger overall immune presence, but the composition and quality of immune infiltrates differed, regardless of tumor subtypes. Black patients had a stronger CD4+/B cell response, and further, a more exhausted CD8+ T cell profile. A signature indicating a higher ratio of exhausted CD8+ T cells to total CD8+ T cells (ExCD8-r) was consistently associated with poorer survival, particularly among hormone receptor (HR)-positive patients. Among HR-negative patients, combinations of the absolute fraction of CD8+ T cells and ExCD8-r signature identified the CD8lowExCD8-rhigh subgroup, the most prevalent among Blacks, with the worst survival. Conclusions Our findings of a distinct exhausted CD8+ T cell signature in Black breast cancer patients indicates an immunobiological basis for their more aggressive disease, and also a rationale for the use of immune checkpoint inhibitors targeting the exhaustion phenotype.

Role of 4-1BB as a Regulator for NKG2D Costimulation in Human CD8+ T Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 923-923
Author(s):  
Young-June Kim ◽  
Myung-Kwan Han ◽  
Hal E. Broxmeyer
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Target Cells ◽  
Costimulatory Receptor ◽  
Cell Responses ◽  
Nkg2d Expression

Abstract NKG2D is a potent costimulatory receptor which is involved in activating various CD8+ T cell responses. Cells undergoing various stresses including tumor formation and virus infection express MHC class I related chain (MIC), a ligand for NKG2D. Thus, MIC acts as a signature molecule of the target cells for CD8+ T cells to recognize in killing. In contrast, MIC also plays a role in impairing effector CD8+ T cell responses because it rapidly internalizes NKG2D from the cell surface. It is unclear how these opposing effects of NKG2D ligation on CD8+ T cell fate are regulated. In this study, we demonstrated that 4-1BB, another costimulatory receptor, might be an important regulator for induction and maintenance of NKG2D expression after its internalization, thereby enhancing effector CD8+ T cell responses. Whereas NKG2D is constitutively expressed on naïve human CD8+ T cells, 4-1BB is induced only by activation. Costimulation of NKG2D with anti-NKG2D and suboptimal anti-CD3 eliminated NKG2D but efficiently induced 4-1BB on naïve CD8+ T cells isolated from human umbilical cord blood, even in the presence of TGF-ß1 which inhibited 4-1BB expression in the absence of NKG2D costimulation. In vitro chromium release assays indicated that the CD8+ T cells costimulated with NKG2D remained low in their cytotoxic activity against C1R B lymphoma cell line expressing MIC which was used as target cells. We found these results despite the fact that the CD8+ T cells were fully activated and expressed 4-1BB and granzyme B at high levels. This is correlated with a lack of NKG2D on the cell surface. Subsequent 4-1BB costimulation restored NKG2D to the cell surface, even in the presence of TGF-ß1. The resulting CD8+ T cells expressing both NKG2D and 4-1BB showed extremely potent cytotoxic activity. Importantly, the NKG2D co-expressed with 4-1BB was unique for being highly refractory to the downregulation by TGF-ß1 and internalization from the cell surface. IL-4 markedly promoted downregulation of NKG2D and 4-1BB expression induced by TGF-ß1, generating a CD8+ T cell type lacking both NKG2D and 4-1BB on the cell surface. These cells were inert and unable to gain cytotoxic as well as proliferative activity, suggesting that CD8+ T cells lacking both NKG2D and 4-1BB may represent terminally incapacitated cells. In summary, NKG2D may be involved in inducing 4-1BB expression and in turn 4-1BB may play a critical role for stabilizing surface NKG2D expression to overcome tumor immune evasion especially in tumor microenvironments enriched with soluble MIC and TGF-ß1. Due to such coupled supports, co-expression of NKG2D and 4-1BB may be a key biomarker for defining effective tumor infiltrating CD8+ T cells that can be used in a clinical setting of immune therapeutic strategies.

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