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IL-15 Superagonist Expands mCD8+ T, NK and NKT Cells after Burn Injury but Fails to Improve Outcome during Burn Wound Infection.
Patil NK, Luan L, Bohannon JK, Guo Y, Hernandez A, Fensterheim B, Sherwood ER
(2016) PLoS One 11: e0148452
MeSH Terms: Adaptive Immunity, Animals, Burns, CD8-Positive T-Lymphocytes, Cytokines, Disease Models, Animal, Humans, Interleukin-15, Killer Cells, Natural, Liver, Lymphocyte Activation, Lymphocyte Count, Lymphocyte Subsets, Male, Mice, Mice, Inbred BALB C, Natural Killer T-Cells, Pseudomonas Infections, Pseudomonas aeruginosa, Receptors, Interleukin-15, Recombinant Fusion Proteins, Spleen, Wound Infection
Show Abstract · Added February 18, 2016
BACKGROUND - Severely burned patients are highly susceptible to opportunistic infections and sepsis, owing to the loss of the protective skin barrier and immunological dysfunction. Interleukin-15 (IL-15) belongs to the IL-2 family of common gamma chain cytokines and stimulates the proliferation and activation of T (specifically memory CD8), NK and NKT cells. It has been shown to preserve T cell function and improve survival during cecal ligation and puncture (CLP)-induced sepsis in mice. However, the therapeutic efficacy of IL-15 or IL-15 superagonist (SA) during infection after burn injury has not been evaluated. Moreover, very few, if any, studies have examined, in detail, the effect of burn injury and infection on the adaptive immune system. Thus, we examined the effect of burn and sepsis on adaptive immune cell populations and the effect of IL-15 SA treatment on the host response to infection.
METHODS - Mice were subjected to a 35% total body surface area burn, followed by wound infection with Pseudomonas aeruginosa. In some experiments, IL-15 SA was administered after burn injury, but before infection. Leukocytes in spleen, liver and peritoneal cavity were characterized using flow cytometry. Bacterial clearance, organ injury and survival were also assessed.
RESULTS - Burn wound infection led to a significant decline in total white blood cell and lymphocyte counts and induced organ injury and sepsis. Burn injury caused decline in CD4+ and CD8+ T cells in the spleen, which was worsened by infection. IL-15 treatment inhibited this decline and significantly increased cell numbers and activation, as determined by CD69 expression, of CD4+, CD8+, B, NK and NKT cells in the spleen and liver after burn injury. However, IL-15 SA treatment failed to prevent burn wound sepsis-induced loss of CD4+, CD8+, B, NK and NKT cells and failed to improve bacterial clearance and survival.
CONCLUSION - Cutaneous burn injury and infection cause significant adaptive immune dysfunction. IL-15 SA does not augment host resistance to burn wound sepsis in mice despite inducing proliferation and activation of lymphocyte subsets.
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23 MeSH Terms
Chronic NF-κB activation links COPD and lung cancer through generation of an immunosuppressive microenvironment in the lungs.
Zaynagetdinov R, Sherrill TP, Gleaves LA, Hunt P, Han W, McLoed AG, Saxon JA, Tanjore H, Gulleman PM, Young LR, Blackwell TS
(2016) Oncotarget 7: 5470-82
MeSH Terms: Animals, Blotting, Western, CD8-Positive T-Lymphocytes, Cells, Cultured, Epithelium, Female, Flow Cytometry, Humans, I-kappa B Kinase, Immunosuppressive Agents, Inflammation, Interleukin-10, Lung, Lung Neoplasms, Macrophages, Alveolar, Male, Mice, Mice, Transgenic, NF-kappa B, Pulmonary Disease, Chronic Obstructive, RNA, Messenger, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, T-Lymphocytes, Regulatory, Transforming Growth Factor beta
Show Abstract · Added February 22, 2016
Nuclear Factor (NF)-κB is positioned to provide the interface between COPD and carcinogenesis through regulation of chronic inflammation in the lungs. Using a tetracycline-inducible transgenic mouse model that conditionally expresses activated IκB kinase β (IKKβ) in airway epithelium (IKTA), we found that sustained NF-κB signaling results in chronic inflammation and emphysema by 4 months. By 11 months of transgene activation, IKTA mice develop lung adenomas. Investigation of lung inflammation in IKTA mice revealed a substantial increase in M2-polarized macrophages and CD4+/CD25+/FoxP3+ regulatory T lymphocytes (Tregs). Depletion of alveolar macrophages in IKTA mice reduced Tregs, increased lung CD8+ lymphocytes, and reduced tumor numbers following treatment with the carcinogen urethane. Alveolar macrophages from IKTA mice supported increased generation of inducible Foxp3+ Tregs ex vivo through expression of TGFβ and IL-10. Targeting of TGFβ and IL-10 reduced the ability of alveolar macrophages from IKTA mice to induce Foxp3 expression on T cells. These studies indicate that sustained activation of NF-κB pathway links COPD and lung cancer through generation and maintenance of a pro-tumorigenic inflammatory environment consisting of alternatively activated macrophages and regulatory T cells.
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26 MeSH Terms
Acute Viral Respiratory Infection Rapidly Induces a CD8+ T Cell Exhaustion-like Phenotype.
Erickson JJ, Lu P, Wen S, Hastings AK, Gilchuk P, Joyce S, Shyr Y, Williams JV
(2015) J Immunol 195: 4319-30
MeSH Terms: Acute Disease, Animals, CD8-Positive T-Lymphocytes, Cluster Analysis, Gene Expression Profiling, Host-Pathogen Interactions, Humans, Lung, Metapneumovirus, Mice, Congenic, Mice, Inbred C57BL, Mice, Knockout, Oligonucleotide Array Sequence Analysis, Paramyxoviridae Infections, Phenotype, Programmed Cell Death 1 Receptor, Respiratory Tract Infections, Spleen, Transcriptome
Show Abstract · Added October 2, 2015
Acute viral infections typically generate functional effector CD8(+) T cells (TCD8) that aid in pathogen clearance. However, during acute viral lower respiratory infection, lung TCD8 are functionally impaired and do not optimally control viral replication. T cells also become unresponsive to Ag during chronic infections and cancer via signaling by inhibitory receptors such as programmed cell death-1 (PD-1). PD-1 also contributes to TCD8 impairment during viral lower respiratory infection, but how it regulates TCD8 impairment and the connection between this state and T cell exhaustion during chronic infections are unknown. In this study, we show that PD-1 operates in a cell-intrinsic manner to impair lung TCD8. In light of this, we compared global gene expression profiles of impaired epitope-specific lung TCD8 to functional spleen TCD8 in the same human metapneumovirus-infected mice. These two populations differentially regulate hundreds of genes, including the upregulation of numerous inhibitory receptors by lung TCD8. We then compared the gene expression of TCD8 during human metapneumovirus infection to those in acute or chronic lymphocytic choriomeningitis virus infection. We find that the immunophenotype of lung TCD8 more closely resembles T cell exhaustion late into chronic infection than do functional effector T cells arising early in acute infection. Finally, we demonstrate that trafficking to the infected lung alone is insufficient for TCD8 impairment or inhibitory receptor upregulation, but that viral Ag-induced TCR signaling is also required. Our results indicate that viral Ag in infected lungs rapidly induces an exhaustion-like state in lung TCD8 characterized by progressive functional impairment and upregulation of numerous inhibitory receptors.
Copyright © 2015 by The American Association of Immunologists, Inc.
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19 MeSH Terms
Histone Deacetylase 3 Is Required for Efficient T Cell Development.
Stengel KR, Zhao Y, Klus NJ, Kaiser JF, Gordy LE, Joyce S, Hiebert SW, Summers AR
(2015) Mol Cell Biol 35: 3854-65
MeSH Terms: Animals, CD4 Antigens, CD4-Positive T-Lymphocytes, CD8 Antigens, CD8-Positive T-Lymphocytes, Cell Differentiation, Gene Deletion, Gene Expression Regulation, Developmental, Histone Deacetylases, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Proto-Oncogene Proteins c-bcl-2, Receptors, Antigen, T-Cell, alpha-beta, T-Lymphocytes, bcl-X Protein
Show Abstract · Added September 28, 2015
Hdac3 is a key target for Hdac inhibitors that are efficacious in cutaneous T cell lymphoma. Moreover, the regulation of chromatin structure is critical as thymocytes transition from an immature cell with open chromatin to a mature T cell with tightly condensed chromatin. To define the phenotypes controlled by Hdac3 during T cell development, we conditionally deleted Hdac3 using the Lck-Cre transgene. This strategy inactivated Hdac3 in the double-negative stages of thymocyte development and caused a significant impairment at the CD8 immature single-positive (ISP) stage and the CD4/CD8 double-positive stage, with few mature CD4(+) or CD8(+) single-positive cells being produced. When Hdac3(-/-) mice were crossed with Bcl-xL-, Bcl2-, or TCRβ-expressing transgenic mice, a modest level of complementation was found. However, when the null mice were crossed with mice expressing a fully rearranged T cell receptor αβ transgene, normal levels of CD4 single-positive cells were produced. Thus, Hdac3 is required for the efficient transit from double-negative stage 4 through positive selection.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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18 MeSH Terms
IL-15 Superagonist-Mediated Immunotoxicity: Role of NK Cells and IFN-γ.
Guo Y, Luan L, Rabacal W, Bohannon JK, Fensterheim BA, Hernandez A, Sherwood ER
(2015) J Immunol 195: 2353-64
MeSH Terms: Animals, Antigens, CD, Antigens, Differentiation, T-Lymphocyte, Body Temperature, CD8-Positive T-Lymphocytes, Cell Proliferation, Cytotoxicity, Immunologic, Dose-Response Relationship, Drug, Female, Flow Cytometry, Granzymes, Humans, Interferon-gamma, Interleukin-15, Interleukin-15 Receptor alpha Subunit, Killer Cells, Natural, Lectins, C-Type, Lymphocyte Activation, Mice, Inbred C57BL, Mice, Knockout, Multiprotein Complexes, Perforin
Show Abstract · Added October 18, 2015
IL-15 is currently undergoing clinical trials to assess its efficacy for treatment of advanced cancers. The combination of IL-15 with soluble IL-15Rα generates a complex termed IL-15 superagonist (IL-15 SA) that possesses greater biological activity than IL-15 alone. IL-15 SA is considered an attractive antitumor and antiviral agent because of its ability to selectively expand NK and memory CD8(+) T (mCD8(+) T) lymphocytes. However, the adverse consequences of IL-15 SA treatment have not been defined. In this study, the effect of IL-15 SA on physiologic and immunologic functions of mice was evaluated. IL-15 SA caused dose- and time-dependent hypothermia, weight loss, liver injury, and mortality. NK (especially the proinflammatory NK subset), NKT, and mCD8(+) T cells were preferentially expanded in spleen and liver upon IL-15 SA treatment. IL-15 SA caused NK cell activation as indicated by increased CD69 expression and IFN-γ, perforin, and granzyme B production, whereas NKT and mCD8(+) T cells showed minimal, if any, activation. Cell depletion and adoptive transfer studies showed that the systemic toxicity of IL-15 SA was mediated by hyperproliferation of activated NK cells. Production of the proinflammatory cytokine IFN-γ, but not TNF-α or perforin, was essential to IL-15 SA-induced immunotoxicity. The toxicity and immunological alterations shown in this study are comparable to those reported in recent clinical trials of IL-15 in patients with refractory cancers and advance current knowledge by providing mechanistic insights into IL-15 SA-mediated immunotoxicity.
Copyright © 2015 by The American Association of Immunologists, Inc.
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22 MeSH Terms
Tumor Necrosis Factor Receptor 2 Restricts the Pathogenicity of CD8(+) T Cells in Mice With Colitis.
Punit S, Dubé PE, Liu CY, Girish N, Washington MK, Polk DB
(2015) Gastroenterology 149: 993-1005.e2
MeSH Terms: Adoptive Transfer, Animals, CD8-Positive T-Lymphocytes, Cell Proliferation, Colitis, Colon, DNA-Binding Proteins, Disease Models, Animal, Gene Expression Regulation, Immunity, Cellular, Interleukin-10, Lymphocyte Activation, Male, Mice, Inbred C57BL, Mice, Knockout, Receptors, Tumor Necrosis Factor, Type II, Signal Transduction, Time Factors
Show Abstract · Added April 12, 2016
BACKGROUND & AIMS - Tumor necrosis factor receptor 2 (TNFR2, Tnfrsf1b) regulates multiple aspects of immune function, but little is known about its role in the immunopathogenesis of inflammatory bowel disease (IBD). We investigated whether TNFR2 restricts the activity of specific immune cell subtypes to protect against the development of colitis in mice.
METHODS - Tnfr2(-/-) mice were crossed with interleukin (Il) 10(-/-) mice, which spontaneously develop colitis, to generate Il10(-/-)Tnfr2(-/-) mice. Colonic tissues were collected from Il10(-/-)Tnfr2(-/-) mice along with Il10(-/-) mice (controls) and analyzed by flow cytometry and histology. Bone marrow was transplanted into Il10(-/-) and Il10(-/-)Tnfr2(-/-) mice from Il10(-/-) or Il10(-/-)Tnfr2(-/-) donors by intravenous injection. CD8(+) T cells were neutralized in Il10(-/-)Tnfr2(-/-) mice by intraperitoneal injection of anti-CD8 or isotype control antibodies. Colitis was induced in Rag2(-/-) mice by intravenous injections of naïve CD8(+) T cells isolated from C57BL/6 or Tnfr2(-/-) mice.
RESULTS - Il10(-/-)Tnfr2(-/-) mice spontaneously developed more severe colitis compared with Il10(-/-) controls, characterized by selective expansion of colonic CD8(+) T cells. Transplantation of TNFR2-deficient bone marrow resulted in significantly increased incidence and severity of colitis. Transcriptome analyses showed that the expression of genes regulated by TNFR2 were specific to CD8(+) T cells and included genes associated with risk for IBD. Depletion of CD8(+) T cells from Il10(-/-)Tnfr2(-/-) mice prevented colonic inflammation. Adoptive transfer of TNFR2-null naïve CD8(+) T cells compared with CD8(+) T cells from control mice increased the severity of colitis that developed in Rag2(-/-) mice.
CONCLUSIONS - TNFR2 protects mice from colitis by inhibiting the expansion of colonic CD8(+) T cells. TNFR2 regulates expression of genes that regulate CD8(+) T cells and have been associated with susceptibility to IBD. Disruption in TNFR2 signaling might therefore be associated with pathogenesis. Strategies to increase levels or activity of TNFR2 and thereby reduce the activity of CD8(+) T cells might be developed to treat IBD patients with CD8(+) T cell dysfunction.
Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
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18 MeSH Terms
Lung CD8+ T Cell Impairment Occurs during Human Metapneumovirus Infection despite Virus-Like Particle Induction of Functional CD8+ T Cells.
Wen SC, Schuster JE, Gilchuk P, Boyd KL, Joyce S, Williams JV
(2015) J Virol 89: 8713-26
MeSH Terms: Animals, Antibodies, Neutralizing, Antibodies, Viral, CD8-Positive T-Lymphocytes, HEK293 Cells, Humans, Lung, Lymphocyte Depletion, Macaca mulatta, Metapneumovirus, Mice, Mice, Inbred C57BL, Mice, Transgenic, Paramyxoviridae Infections, Programmed Cell Death 1 Receptor, Respiratory Tract Infections, Vaccination, Vaccines, Virus-Like Particle, Viral Fusion Proteins, Viral Matrix Proteins, Virus Replication
Show Abstract · Added October 2, 2015
UNLABELLED - Human metapneumovirus (HMPV) is a major cause of respiratory disease in infants, the elderly, and immunocompromised individuals worldwide. There is currently no licensed HMPV vaccine. Virus-like particles (VLPs) are an attractive vaccine candidate because they are noninfectious and elicit a neutralizing antibody response. However, studies show that serum neutralizing antibodies are insufficient for complete protection against reinfection and that adaptive T cell immunity is important for viral clearance. HMPV and other respiratory viruses induce lung CD8(+) T cell (TCD8) impairment, mediated by programmed death 1 (PD-1). In this study, we generated HMPV VLPs by expressing the fusion and matrix proteins in mammalian cells and tested whether VLP immunization induces functional HMPV-specific TCD8 responses in mice. C57BL/6 mice vaccinated twice with VLPs and subsequently challenged with HMPV were protected from lung viral replication for at least 20 weeks postimmunization. A single VLP dose elicited F- and M-specific lung TCD8s with higher function and lower expression of PD-1 and other inhibitory receptors than TCD8s from HMPV-infected mice. However, after HMPV challenge, lung TCD8s from VLP-vaccinated mice exhibited inhibitory receptor expression and functional impairment similar to those of mice experiencing secondary infection. HMPV challenge of VLP-immunized μMT mice also elicited a large percentage of impaired lung TCD8s, similar to mice experiencing secondary infection. Together, these results indicate that VLPs are a promising vaccine candidate but do not prevent lung TCD8 impairment upon HMPV challenge.
IMPORTANCE - Human metapneumovirus (HMPV) is a leading cause of acute respiratory disease for which there is no licensed vaccine. Virus-like particles (VLPs) are an attractive vaccine candidate and induce antibodies, but T cell responses are less defined. Moreover, HMPV and other respiratory viruses induce lung CD8(+) T cell (TCD8) impairment mediated by programmed death 1 (PD-1). In this study, HMPV VLPs containing viral fusion and matrix proteins elicited epitope-specific TCD8s that were functional with low PD-1 expression. Two VLP doses conferred sterilizing immunity in C57BL/6 mice and facilitated HMPV clearance in antibody-deficient μMT mice without enhancing lung pathology. However, regardless of whether responding lung TCD8s had previously encountered HMPV antigens in the context of VLPs or virus, similar proportions were impaired and expressed comparable levels of PD-1 upon viral challenge. These results suggest that VLPs are a promising vaccine candidate but do not prevent lung TCD8 impairment upon HMPV challenge.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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21 MeSH Terms
Innate and virtual memory T cells in man.
Van Kaer L
(2015) Eur J Immunol 45: 1916-20
MeSH Terms: Animals, CD8-Positive T-Lymphocytes, Humans, Immunity, Innate, Immunologic Memory, Mice, T-Lymphocyte Subsets
Show Abstract · Added September 28, 2015
A hallmark of the antigen-specific B and T lymphocytes of the adaptive immune system is their capacity to "remember" pathogens long after they are first encountered, a property that forms the basis for effective vaccine development. However, studies in mice have provided strong evidence that some naive T cells can develop characteristics of memory T cells in the absence of foreign antigen encounters. Such innate memory T cells may develop in response to lymphopenia or the presence of high levels of the cytokine IL-4, and have also been identified in unmanipulated animals, a phenomenal referred to as "virtual memory." While the presence of innate memory T cells in mice is now widely accepted, their presence in humans has not yet been fully validated. In this issue of the European Journal of Immunology, Jacomet et al. [Eur. J. Immunol. 2015. 45:1926-1933] provide the best evidence to date for innate memory T cells in humans. These findings may contribute significantly to our understanding of human immunity to microbial pathogens and tumors.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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7 MeSH Terms
Discovering protective CD8 T cell epitopes--no single immunologic property predicts it!
Gilchuk P, Hill TM, Wilson JT, Joyce S
(2015) Curr Opin Immunol 34: 43-51
MeSH Terms: Animals, Antigen Presentation, CD8-Positive T-Lymphocytes, Databases, Factual, Epitopes, T-Lymphocyte, Humans, Receptors, Antigen, T-Cell, Vaccines
Show Abstract · Added October 2, 2015
Once a burgeoning field of study, over the past decade or so, T cell epitope discovery has lost some luster. The contributory factors perchance are the general notion that any newly discovered epitope will reveal very little about an immune response and that knowledge of epitopes are less critical for vaccine design. Despite these notions, the breadth and depth of T cell epitopes derived from clinically important microbial agents of human diseases largely remain ill defined. We review here a flurry of recent reports that have rebirthed the field. These reports reveal that epitope discovery is an essential step toward rational vaccine design and critical for monitoring vaccination efficacy. The new findings also indicate that neither immunogenicity nor immunodominance predict protective immunity. Hence, an immunogenic epitope is but a peptide unless proven protective against disease.
Copyright © 2015. Published by Elsevier Ltd.
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8 MeSH Terms
Role of type I interferon signaling in human metapneumovirus pathogenesis and control of viral replication.
Hastings AK, Erickson JJ, Schuster JE, Boyd KL, Tollefson SJ, Johnson M, Gilchuk P, Joyce S, Williams JV
(2015) J Virol 89: 4405-20
MeSH Terms: Analysis of Variance, Animals, Antigen-Presenting Cells, CD8-Positive T-Lymphocytes, Flow Cytometry, Gene Expression Regulation, Hepatitis A Virus Cellular Receptor 2, Humans, Interferon Type I, Metapneumovirus, Mice, Mice, Inbred C57BL, Mice, Knockout, Oximetry, Paramyxoviridae Infections, Real-Time Polymerase Chain Reaction, Receptors, Virus, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Virus Replication
Show Abstract · Added October 2, 2015
UNLABELLED - Type I IFN signaling, which is initiated through activation of the alpha interferon receptor (IFNAR), regulates the expression of proteins that are crucial contributors to immune responses. Paramyxoviruses, including human metapneumovirus (HMPV), have evolved mechanisms to inhibit IFNAR signaling, but the specific contribution of IFNAR signaling to the control of HMPV replication, pathogenesis, and adaptive immunity is unknown. We used IFNAR-deficient (IFNAR(-/-)) mice to assess the effect of IFNAR signaling on HMPV replication and the CD8(+) T cell response. HMPV-infected IFNAR(-/-) mice had a higher peak of early viral replication but cleared the virus with kinetics similar to those of wild-type (WT) mice. However, IFNAR(-/-) mice infected with HMPV displayed less airway dysfunction and lung inflammation. CD8(+) T cells of IFNAR(-/-) mice after HMPV infection expressed levels of the inhibitory receptor programmed death 1 (PD-1) similar to those of WT mice. However, despite lower expression of inhibitory programmed death ligand 1 (PD-L1), HMPV-specific CD8(+) T cells of IFNAR(-/-) mice were more functionally impaired than those of WT mice and upregulated the inhibitory receptor Tim-3. Analysis of the antigen-presenting cell subsets in the lungs revealed that the expansion of PD-L1(low) dendritic cells (DCs), but not PD-L1(high) alveolar macrophages, was dependent on IFNAR signaling. Collectively, our results indicate a role for IFNAR signaling in the early control of HMPV replication, disease progression, and the development of an optimal adaptive immune response. Moreover, our findings suggest an IFNAR-independent mechanism of lung CD8(+) T cell impairment.
IMPORTANCE - Human metapneumovirus (HMPV) is a leading cause of acute respiratory illness. CD8(+) T cells are critical for clearing viral infection, yet recent evidence shows that HMPV and other respiratory viruses induce CD8(+) T cell impairment via PD-1-PD-L1 signaling. We sought to understand the role of type I interferon (IFN) in the innate and adaptive immune responses to HMPV by using a mouse model lacking IFN signaling. Although HMPV titers were higher in the absence of type I IFN, virus was nonetheless cleared and mice were less ill, indicating that type I IFN is not required to resolve HMPV infection but contributes to pathogenesis. Further, despite lower levels of the inhibitory ligand PD-L1 in mice lacking type I IFN, CD8(+) T cells were more impaired in these mice than in WT mice. Our data suggest that specific antigen-presenting cell subsets and the inhibitory receptor Tim-3 may contribute to CD8(+) T cell impairment.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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20 MeSH Terms