scholarly journals Histone Acetyltransferase CBP Is Vital To Demarcate Conventional and Innate CD8+ T-Cell Development

2009 ◽  
Vol 29 (14) ◽  
pp. 3894-3904 ◽  
Author(s):  
Tomofusa Fukuyama ◽  
Lawryn H. Kasper ◽  
Fayçal Boussouar ◽  
Trushar Jeevan ◽  
Jan van Deursen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protein Tyrosine Kinase ◽  
Interleukin 2 ◽  
Effector Memory ◽  
Cell Phenotype ◽  
Creb Binding Protein ◽  
Thymic Development ◽  
Nuclear Component ◽  
Single Positive

ABSTRACT Defining the chromatin modifications and transcriptional mechanisms that direct the development of different T-cell lineages is a major challenge in immunology. The transcriptional coactivators CREB binding protein (CBP) and the closely related p300, which comprise the KAT3 family of histone/protein lysine acetyltransferases, interact with over 50 T-lymphocyte-essential transcriptional regulators. We show here that CBP, but not p300, modulates the thymic development of conventional adaptive T cells versus those having unconventional innate functions. Conditional inactivation of CBP in the thymus yielded CD8 single-positive (SP) thymocytes with an effector-, memory-, or innate-like T-cell phenotype. In this regard, CD8 SP thymocytes in CBP mutant mice were phenotypically similar to those reported for Itk and Rlk protein tyrosine kinase mutants, including the increased expression of the T-cell master regulatory transcription factor eomesodermin (Eomes) and the interleukin-2 and -15 receptor beta chain (CD122) and an enhanced ability to rapidly produce gamma interferon. CBP was required for the expression of the Itk-dependent genes Egr2, Egr3, and Il2, suggesting that CBP helps mediate Itk-responsive transcription. CBP therefore defines a nuclear component of the signaling pathways that demarcate the development of innate and adaptive naïve CD8+ T cells in the thymus.

Combination cancer immunotherapy targeting PD-1 and GITR can rescue CD8+T cell dysfunction and maintain memory phenotype

2018 ◽  
Vol 3 (29) ◽  
pp. eaat7061 ◽  
Author(s):  
Bei Wang ◽  
Wen Zhang ◽  
Vladimir Jankovic ◽  
Jacquelynn Golubov ◽  
Patrick Poon ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
Cancer Immunotherapy ◽  
Effector Memory ◽  
Cell Phenotype ◽  
Checkpoint Inhibition ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

Most patients with cancer do not develop durable antitumor responses after programmed cell death protein 1 (PD-1) or programmed cell death ligand 1(PD-L1) checkpoint inhibition monotherapy because of an ephemeral reversal of T cell dysfunction and failure to promote long-lasting immunological T cell memory. Activating costimulatory pathways to induce stronger T cell activation may improve the efficacy of checkpoint inhibition and lead to durable antitumor responses. We performed single-cell RNA sequencing of more than 2000 tumor-infiltrating CD8+T cells in mice receiving both PD-1 and GITR (glucocorticoid-induced tumor necrosis factor receptor–related protein) antibodies and found that this combination synergistically enhanced the effector function of expanded CD8+T cells by restoring the balance of key homeostatic regulators CD226 and T cell immunoreceptor with Ig and ITIM domains (TIGIT), leading to a robust survival benefit. Combination therapy decreased CD8+T cell dysfunction and induced a highly proliferative precursor effector memory T cell phenotype in a CD226-dependent manner. PD-1 inhibition rescued CD226 activity by preventing PD-1–Src homology region 2 (SHP2) dephosphophorylation of the CD226 intracellular domain, whereas GITR agonism decreased TIGIT expression. Unmasking the molecular pathways driving durable antitumor responses will be essential to the development of rational approaches to optimizing cancer immunotherapy.

scholarly journals Short-Lived Effector CD8 T Cells Induced by Genetically Attenuated Malaria Parasite Vaccination Express CD11c

2013 ◽  
Vol 81 (11) ◽  
pp. 4171-4181 ◽  
Author(s):  
Laura A. Cooney ◽  
Megha Gupta ◽  
Sunil Thomas ◽  
Sebastian Mikolajczak ◽  
Kimberly Y. Choi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Inflammatory Cytokines ◽  
Plasmodium Yoelii ◽  
T Cell Response ◽  
Parasite Development ◽  
Effector Memory ◽  
Cell Phenotype ◽  
Effector Cells ◽  
Ifn Γ

ABSTRACTVaccination with a single dose of genetically attenuated malaria parasites can induce sterile protection against sporozoite challenge in the rodentPlasmodium yoeliimodel. Protection is dependent on CD8+T cells, involves perforin and gamma interferon (IFN-γ), and is correlated with the expansion of effector memory CD8+T cells in the liver. Here, we have further characterized vaccine-induced changes in the CD8+T cell phenotype and demonstrated significant upregulation of CD11c on CD3+CD8b+T cells in the liver, spleen, and peripheral blood. CD11c+CD8+T cells are predominantly CD11ahiCD44hiCD62L−, indicative of antigen-experienced effector cells. Followingin vitrorestimulation with malaria-infected hepatocytes, CD11c+CD8+T cells expressed inflammatory cytokines and cytotoxicity markers, including IFN-γ, tumor necrosis factor alpha (TNF-α), interleukin-2 (IL-2), perforin, and CD107a. CD11c−CD8+T cells, on the other hand, expressed negligible amounts of all inflammatory cytokines and cytotoxicity markers tested, indicating that CD11c marks multifunctional effector CD8+T cells. Coculture of CD11c+, but not CD11c−, CD8+T cells with sporozoite-infected primary hepatocytes significantly inhibited liver-stage parasite development. Tetramer staining for the immunodominant circumsporozoite protein (CSP)-specific CD8+T cell epitope demonstrated that approximately two-thirds of CSP-specific cells expressed CD11c at the peak of the CD11c+CD8+T cell response, but CD11c expression was lost as the CD8+T cells entered the memory phase. Further analyses showed that CD11c+CD8+T cells are primarily KLRG1+CD127−terminal effectors, whereas all KLRG1−CD127+memory precursor effector cells are CD11c−CD8+T cells. Together, these results suggest that CD11c marks a subset of highly inflammatory, short-lived, antigen-specific effector cells, which may play an important role in eliminating infected hepatocytes.

scholarly journals NKAP is required for T cell maturation and acquisition of functional competency

2011 ◽  
Vol 208 (6) ◽  
pp. 1291-1304 ◽  
Author(s):  
Fan-Chi Hsu ◽  
Anthony G. Pajerowski ◽  
Molly Nelson-Holte ◽  
Rhianna Sundsbak ◽  
Virginia Smith Shapiro
Keyword(s):  
T Cells ◽  
T Cell ◽  
Conditional Knockout ◽  
Cell Maturation ◽  
Intrinsic Defect ◽  
Thymic Development ◽  
Cell Pool ◽  
Single Positive ◽  
Maturation Defect ◽  
T Cell Maturation

Newly generated T cells are unable to respond to antigen/MHC. Rather, post-selection single-positive thymocytes must undergo T cell maturation to gain functional competency and enter the long-lived naive peripheral T cell pool. This process is poorly understood, as no gene specifically required for T cell maturation has been identified. Here, we demonstrate that loss of the transcriptional repressor NKAP results in a complete block in T cell maturation. In CD4-cre NKAP conditional knockout mice, thymic development including positive selection occurs normally, but there is a cell-intrinsic defect in the peripheral T cell pool. All peripheral naive CD4-cre NKAP conditional knockout T cells were found to be functionally immature recent thymic emigrants. This defect is not simply in cell survival, as the T cell maturation defect was not rescued by a Bcl-2 transgene. Thus, NKAP is required for T cell maturation and the acquisition of functional competency.

scholarly journals Protective Immunity against Experimental Pulmonary Cryptococcosis in T Cell-Depleted Mice

2011 ◽  
Vol 18 (5) ◽  
pp. 717-723 ◽  
Author(s):  
Karen L. Wozniak ◽  
Mattie L. Young ◽  
Floyd L. Wormley
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protective Immunity ◽  
Effector Memory ◽  
Cell Phenotype ◽  
Cell Mediated Immunity ◽  
Wild Type ◽  
Pulmonary Cryptococcosis ◽  
Content Type ◽  
Immunocompetent Mice

ABSTRACTIndividuals with defects in T cell-mediated immunity (CMI) are highly susceptible to infection withCryptococcus neoformans. The purpose of these studies was to determine if protection against experimental pulmonary cryptococcosis can be generated in T cell-deficient hosts. BALB/c mice were depleted of CD4+and/or CD8+T cells or given an isotype control antibody prior to vaccination with aC. neoformansstrain, designated H99γ, previously shown to induce protection againstC. neoformansinfection in immunocompetent mice. Mice depleted of CD4+or CD8+T cells, but not both subsets, survived an acute pulmonary infection withC. neoformansstrain H99γ and a subsequent second challenge with wild-typeC. neoformansstrain H99. We observed a significant increase in the percentage of CD4+and CD8+T cells expressing the activation marker CD69 in the lungs of mice immunized withC. neoformansstrain H99γ prior to a secondary challenge with wild-type cryptococci. CD4+T cells within the lungs of immunized mice also appeared to acquire a predominantly activated effector memory cell phenotype (CD69+CD44+CCR7−CD45RB−CD62L−) following a second pulmonary challenge with wild-typeC. neoformans, compared to CD4+T cells from naïve mice. Lastly, immunization of immunocompetent mice withC. neoformansstrain H99γ prior to depletion of CD4+and/or CD8+T cells resulted in significant protection against a second challenge with wild-typeC. neoformans. Our studies demonstrate that protective immunity against pulmonary cryptococcosis can be generated in immunosuppressed hosts, thus supporting the development of cryptococcal vaccines.

scholarly journals A Novel Gene Essential for the Development of Single Positive Thymocytes

2009 ◽  
Vol 29 (18) ◽  
pp. 5128-5135 ◽  
Author(s):  
Kiyokazu Kakugawa ◽  
Takuwa Yasuda ◽  
Ikuo Miura ◽  
Ayako Kobayashi ◽  
Hitomi Fukiage ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mutant Mice ◽  
Cell Phenotype ◽  
Double Positive ◽  
Cell Stage ◽  
Class I Mhc ◽  
Orphan Gene ◽  
Novel Gene ◽  
Single Positive

ABSTRACT A critical step during intrathymic T-cell development is the transition of CD4+ CD8+ double-positive (DP) cells to the major histocompatibility complex class I (MHC-I)-restricted CD4− CD8+ and MHC-II-restricted CD4+ CD8− single-positive (SP) cell stage. Here, we identify a novel gene that is essential for this process. Through the T-cell phenotype-based screening of N-ethyl-N-nitrosourea (ENU)-induced mutant mice, we established a mouse line in which numbers of CD4 and CD8 SP thymocytes as well as peripheral CD4 and CD8 T cells were dramatically reduced. Using linkage analysis and DNA sequencing, we identified a missense point mutation in a gene, E430004N04Rik (also known as themis), that does not belong to any known gene family. This orphan gene is expressed specifically in DP and SP thymocytes and peripheral T cells, whereas in mutant thymocytes the levels of protein encoded by this gene were drastically reduced. We generated E430004N04Rik-deficient mice, and their phenotype was virtually identical to that of the ENU mutant mice, thereby confirming that this gene is essential for the development of SP thymocytes.

scholarly journals Application of a Standardized Flow Cytometry Panel for Defining and Monitoring the Immunophenotype of CAR-T Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5626-5626
Author(s):  
Irene Scarfò ◽  
Kathleen Gallagher ◽  
Marcela V. Maus ◽  
Rebecca Larson ◽  
Maegan Sheehan ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Unmet Need ◽  
Central Memory ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Cell Phenotype ◽  
Memory T Cell ◽  
Car T

Chimeric antigen receptor T-cells (CAR-T) have emerged as an extremely promising therapy for hematological malignancies. The immunophenotype of apheresis material and the CAR-T cell product is known to be predictive of the likelihood of response to treatment of certain malignancies. Central memory and stem cell-like memory T cell phenotypes are associated with a more sustained proliferative response and long-term CAR-T persistence (Fraietta et al, Nature Medicine, 2018). There is an unmet need for standardized methods and reagents to reliably profile the memory phenotype of CAR-Ts to better evaluate product quality, and support improvements in CAR-T manufacturing. The BD Biosciences dried memory T-cell panel contains a pre-validated mixture of 7 antibodies for the identification of naïve, stem cell memory, central memory and effector memory CD4+ and CD8+ T cell subsets. The pre-mixed dried antibody tube offers consistency in staining profiles over time and reduces the risk of operator errors. Additional drop-in antibodies can complement the panel and enable more in-depth evaluation of the T cell phenotype. Here we demonstrate the use of this panel with drop-in markers to monitor changes in expression of PD-1, TIM-3, LAG-3, HLA-DR, CD45RO, and CXCR3 on T cells transduced to express our novel anti-CD37 CAR. Cells were stained at day 0 prior to transduction, day 7, and following resting and re-stimulation, and acquired on a 12 color BD FACS Lyric. The use of a standardized memory T-cell panel will allow us to more accurately evaluate how T-cell phenotype impacts on the efficacy and longevity of response in patients receiving CAR-T therapies. Disclosures Maus: INFO PENDING: Other: INFO PENDING. Bornheimer:BD Biosciences: Employment. Hanley:BD Biosciences: Employment. Frigault:Novartis: Patents & Royalties: Royalty; Arcellx, Celgene, Foundation Medicine, Kite/Gilead, Nkarta, Novartis, and Xenetic: Consultancy.

scholarly journals Persistent memory CD4+ and CD8+ T-cell responses in recovered severe acute respiratory syndrome (SARS) patients to SARS coronavirus M antigen

2007 ◽  
Vol 88 (10) ◽  
pp. 2740-2748 ◽  
Author(s):  
Litao Yang ◽  
Hui Peng ◽  
Zhaoling Zhu ◽  
Gang Li ◽  
Zitong Huang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Severe Acute Respiratory Syndrome ◽  
Flow Cytometric Analysis ◽  
Memory Cell ◽  
T Cell Response ◽  
M Protein ◽  
Effector Memory ◽  
Cell Phenotype ◽  
Human T Cell

The membrane (M) protein of severe acute respiratory syndrome coronavirus (SARS-CoV) is a major glycoprotein with multiple biological functions. In this study, we found that memory T cells against M protein were persistent in recovered SARS patients by detecting gamma interferon (IFN-γ) production using ELISA and ELISpot assays. Flow cytometric analysis showed that both CD4+ and CD8+ T cells were involved in cellular responses to SARS-CoV M antigen. Furthermore, memory CD8+ T cells displayed an effector memory cell phenotype expressing CD45RO− CCR7− CD62L−. In contrast, the majority of IFN-γ + CD4+ T cells were central memory cells with the expression of CD45RO+ CCR7+ CD62L−. The epitope screening from 30 synthetic overlapping peptides that cover the entire SARS-CoV M protein identified four human T-cell immunodominant peptides, p21-44, p65-91, p117-140 and p200-220. All four immunodominant peptides could elicit cellular immunity with a predominance of CD8+ T-cell response. This data may have important implication for developing SARS vaccines.

scholarly journals Expression of Senescence Marker TIGIT Identifies Polyfunctional Donor-Reactive CD4+ T Cells Preferentially Lost After Kidney Transplantation

2021 ◽  
Vol 12 ◽  
Author(s):  
Amy C. J. van der List ◽  
Nicolle H. R. Litjens ◽  
Mariska Klepper ◽  
Michiel G. H. Betjes
Keyword(s):  
T Cells ◽  
Kidney Transplantation ◽  
T Cell ◽  
Expression Profile ◽  
Cd4 T Cells ◽  
Effector Memory ◽  
Cell Phenotype ◽  
Kidney Transplant Recipients ◽  
Post Transplantation ◽  
Cytokine Expression Profile

Development of T-cell hyporesponsiveness to donor antigen may explain the substantial decreased risk for acute rejection in the years following kidney transplantation. The underlying mechanisms of donor-specific hyporesponsiveness (DSH) are largely unknown but may allow for lowering of immunosuppressive medication. Due to the onset of DSH being more rapid and pronounced in older recipients (+55 years), we hypothesized that immunosenescence/exhaustion of T lymphocytes would be a contributing factor. This study tested whether donor-reactive recipient T cells become hyporesponsive due to exhaustion from continuous stimulation by donor antigen. Circulating donor-reactive T cells of both young and elderly stable kidney transplant recipients (N=17) before and 3-5 years after transplantation were analyzed at the single cell level for expression of exhaustion markers by multi-parameter flow cytometry followed by unsupervised and unbiased clustering. Clusters containing cells of a particular expression profile with significant differential abundance after transplantation were identified and further analyzed. Unexpectedly, our results do not demonstrate an increase in exhausted donor antigen-reactive T cells post transplantation. Instead, we demonstrate a significant decrease in donor antigen-reactive CD4+ T cells expressing T cell immunoglobulin and ITIM domain (TIGIT) long after transplantation. Further analysis at earlier timepoints indicated that this decrease is already present at six months post transplantation. Characterization of these CD4+ T donor-reactive cells expressing TIGIT revealed them to have a predominantly central and effector memory T cell phenotype and a highly poly-functional cytokine expression profile. This study has therefore identified TIGIT as a marker for a previously undescribed polyfunctional donor-reactive CD4+ T cell population whose decline following kidney transplantation may explain development of DSH.

scholarly journals Early Deletion and Late Positive Selection of T-Cells Expressing a Male-Specific Receptor in T-Cell Receptor Transgenic Mice

1990 ◽  
Vol 1 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Hung Sia Teh ◽  
Hiroyuki Kishi ◽  
Bernadette Scott ◽  
Peter Borgulya ◽  
Harald Von Boehmer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
Positive Selection ◽  
T Cell Receptor ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Early Expression ◽  
Single Positive ◽  
Selection Of

The ontogeny of T cells in T-cell receptor (TCR) transgenic mice, which express a transgenicαβheterodimer, specific for the male (H-Y) antigen in association with H-2Db, was determined. The transgenicαchain was expressed on about 10% of the fetal thymocytes on day 14 of gestation. About 50% of day-15 fetal thymocytes expressed bothαandβtranschains and virtually all fetal thymocytes expressed the transgenicαβheterodimer by day 17. The early expression of the transgenic TCR on CD4-8-thymocytes prevented the development ofγδcells, and led to accelerated growth of thymocytes and an earlier expression of CD4 and CD8 molecules. Up to day 17, no significant differences in T-cell development could be detected between female and male thymuses. By day 18 of gestation, the male transgenic thymus contained more CD4-8-thymocytes than the female transgenic thymus. The preponderance of CD4-8-thymocytes in the male transgenic thymus increased until birth and was a consequence of the deletion of the CD4+8+thymocytes and their CD4-8+precursors. By the time of birth, the male transgenic thymus contained half the number of cells as the female transgenic thymus. The deletion of autospecific precursor cells in the male transgenic mouse began only at day 18 of gestation, despite the fact that the ligand could already be detected by day 16.The preferential accumulation of CD4-8+T cells, which expressed a high density of the transgenic TCR, occurred only after birth and was .obvious in 6-week-old female thymus. These data support the hypothesis that the positive selection of T cells expressing this transgenic heterodimer may involve two steps, i.e., the commitment of CD4+8+thymocytes to the CD4-8+lineage following the interaction of the transgenic TCR with restricting major histocompatibility molecules, followed by a slow conversion of CD4+8+thymocytes into CD4-8+T cells.In normal mice, the precursors of CD+4+8 and single positive thymocytes have the CD4-8-CD3-J11d+(or M1/69+) phenotype. Because of the early expression of the transgenicαβheterodimer, this population was not detected in adult transgenic mice. All CD4-8-M1/ 69+cells expressed the transgenic receptor associated with CD3 and could be readily grown in media containing T-cell lectins and interleukin 2.

Marrow-Infiltrating T Cells In Patients with Chronic Lymphocytic Leukemia Display Markers of Functional Impairment and Express PD-1

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2417-2417
Author(s):  
Ursula Hainz ◽  
Quinlan L. Sievers ◽  
Kristen Stevenson ◽  
Natalie R. Goldstein ◽  
David Dorfman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Regulatory T Cells ◽  
Cd8 T Cells ◽  
Immunohistochemical Staining ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
Effector Memory ◽  
Cell Phenotype

Abstract Abstract 2417 Marrow is a major site of disease development and progression for chronic lymphocytic leukemia (CLL), as well as a priming site for antigen-specific T cells and a reservoir for memory T cells. To determine the extent to which T cells in the marrow microenvironment have an altered phenotype and function in CLL, we analyzed the immunophenotypic characteristics of marrow-infiltrating T cells of 18 CLL patients compared to 11 normal donors. Chemotherapy-naïve CLL patients (n=7) possessed comparable quantities of marrow T cells compared to normal donors (median CD8+ T cells/μl = CLL 904 vs normal 1247; median CD4+ T cells/μl = CLL 1975 vs normal 1110). However, we identified several aberrant characteristics among T cells infiltrating the marrow of CLL patients. First, the ratio of CD8+ to regulatory T cells (CD4+CD25+FOXP3+) was depressed (median ratio CLL 14 vs normal 41), indicating more regulatory T cells per effector T cells in CLL. Second, compared to normal marrow T cells, CLL marrow contained proportionally fewer functional effector CD8+ T cells (CD27+CD28+)(median normal 57%, CLL 48%) and more immunosenescent cells (CD27-CD28-)(median normal 21%, CLL 30%). Third, the T cell differentiation state of CLL CD8+ T cells was skewed to favor a phenotype of increased terminal differentiation (CD45RA+CCR7-)(median CLL 55% vs normal 40%), and decreased naïve (CD45RA+CCR7+) cells (median CLL 21% vs normal 31%) compared to normal donors. These differences were further accentuated in CLL samples collected within 4 months from treatment with conventional chemotherapy (n=11). Finally, by immunohistochemical staining of CLL marrow biopsies, we observed marrow-infiltrating lymphocytes to express PD-1 (mean of infiltrating T cells, untreated CLL 12%, treated CLL 35%, present even >6 months after therapy), a marker associated both with immuno-activation and inhibition. While the majority of PD-1+ CD8 T cells of normal donors (n=5) and treated CLL patients (n=4) were differentiated towards effector memory (CD45RA-CCR7-) cells (median normal 46% vs untreated CLL 16%, p=0.07; treated CLL 61%), the PD-1+ T cells from untreated CLL patients (n=5) were terminally differentiated (CD45RA+CCR7+)(median normal 23% vs untreated CLL 65%, p=0.04; treated CLL 24%). These results indicate an exhausted rather than an activated T cell phenotype in untreated patients. Paired immunophenotypic analysis on blood and marrow from the same individuals (n=9) demonstrated an increased percentage and intensity of PD-1 expression on T cells from marrow compared to blood (percentage CD8+ T cells BM vs blood p = 0.05). Interestingly, PD-1 was also detected on CLL cells (n=16) but not normal B cells (median normal 0%, vs CLL 17%, p = 0.004). The ligand for PD-1, PD-L1, was detected in the marrow vasculature by immunohistochemical staining of biopsies, suggesting that the marrow microenvironment plays a role in the induction of PD-1 associated immunosuppression. Ligation of blood PD-L1 on CLL-T cells led to a 2-fold decrease in activation (measured as CD69 expression) of CD3/CD28 stimulated patient T cells. In summary, we identify several phenotypic and functional alterations within marrow-infiltrating T cells of CLL patients. We speculate these together may contribute to impaired priming of host immunity against the tumor. The PD-1 pathway appears to be activated in CLL, especially in the setting of chemotherapeutic treatment. Since anti-PD1 antibodies are now clinically available, it may be possible to target this pathway to improve anti-tumor responses. Disclosures: No relevant conflicts of interest to declare.

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