scholarly journals CD8+T Cell Exhaustion, Suppressed Gamma Interferon Production, and Delayed Memory Response Induced by Chronic Brucella melitensis Infection

2015 ◽  
Vol 83 (12) ◽  
pp. 4759-4771 ◽  
Author(s):  
Marina Durward-Diioia ◽  
Jerome Harms ◽  
Mike Khan ◽  
Cherisse Hall ◽  
Judith A. Smith ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adoptive Transfer ◽  
Chronic Infection ◽  
Brucella Melitensis ◽  
Gamma Interferon ◽  
T Cell Exhaustion ◽  
Content Type ◽  
Cell Exhaustion ◽  
Ifn Γ

Brucella melitensisis a well-adapted zoonotic pathogen considered a scourge of mankind since recorded history. In some cases, initial infection leads to chronic and reactivating brucellosis, incurring significant morbidity and economic loss. The mechanism by whichB. melitensissubverts adaptive immunological memory is poorly understood. Previous work has shown thatBrucella-specific CD8+T cells express gamma interferon (IFN-γ) and can transition to long-lived memory cells but are not polyfunctional. In this study, chronic infection of mice withB. melitensisled to CD8+T cell exhaustion, manifested by programmed cell death 1 (PD-1) and lymphocyte activation gene 3 (LAG-3) expression and a lack of IFN-γ production. TheB. melitensis-specific CD8+T cells that produced IFN-γ expressed less IFN-γ per cell than did CD8+cells from uninfected mice. Both memory precursor (CD8+LFA1HICD127HIKLRG1LO) and long-lived memory (CD8+CD27HICD127HIKLRG1LO) cells were identified during chronic infection. Interestingly, after adoptive transfer, mice receiving cells from chronically infected animals were able to contain infection more rapidly than recipients of cells from acutely infected or uninfected donors, although the proportions of exhausted CD8+T cells increased after adoptive transfer in both challenged and unchallenged recipients. CD8+T cells of challenged recipients initially retained the stunted IFN-γ production found prior to transfer, and cells from acutely infected mice were never seen to transition to either memory subset at all time points tested, up to 30 days post-primary infection, suggesting a delay in the generation of memory. Here we have identified defects inBrucella-responsive CD8+T cells that allow chronic persistence of infection.

scholarly journals Bovine Immunoinhibitory Receptors Contribute to Suppression of Mycobacterium avium subsp. paratuberculosis-Specific T-Cell Responses

2015 ◽  
Vol 84 (1) ◽  
pp. 77-89 ◽  
Author(s):  
Tomohiro Okagawa ◽  
Satoru Konnai ◽  
Asami Nishimori ◽  
Ryoyo Ikebuchi ◽  
Seiko Mizorogi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mycobacterium Avium ◽  
T Cell Responses ◽  
T Cell Exhaustion ◽  
Content Type ◽  
Cell Exhaustion ◽  
Mhc Ii ◽  
Cell Responses ◽  
Ifn Γ

Johne's disease (paratuberculosis) is a chronic enteritis in cattle that is caused by intracellular infection withMycobacterium aviumsubsp.paratuberculosis. This infection is characterized by the functional exhaustion of T-cell responses toM. aviumsubsp.paratuberculosisantigens during late subclinical and clinical stages, presumably facilitating the persistence of this bacterium and the formation of clinical lesions. However, the mechanisms underlying T-cell exhaustion in Johne's disease are poorly understood. Thus, we performed expression and functional analyses of the immunoinhibitory molecules programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) and lymphocyte activation gene 3 (LAG-3)/major histocompatibility complex class II (MHC-II) inM. aviumsubsp.paratuberculosis-infected cattle during the late subclinical stage. Flow cytometric analyses revealed the upregulation of PD-1 and LAG-3 in T cells in infected animals, which suffered progressive suppression of interferon gamma (IFN-γ) responses to theM. aviumsubsp.paratuberculosisantigen. In addition, PD-L1 and MHC-II were expressed on macrophages from infected animals, consistent with PD-1 and LAG-3 pathways contributing to the suppression of IFN-γ responses during the subclinical stages ofM. aviumsubsp.paratuberculosisinfection. Furthermore, dual blockade of PD-L1 and LAG-3 enhancedM. aviumsubsp.paratuberculosis-specific IFN-γ responses in blood from infected animals, andin vitroLAG-3 blockade enhanced IFN-γ production fromM. aviumsubsp.paratuberculosis-specific CD4+and CD8+T cells. Taken together, the present data indicate thatM. aviumsubsp.paratuberculosis-specific T-cell exhaustion is in part mediated by PD-1/PD-L1 and LAG-3/MHC-II interactions and that LAG-3 is a molecular target for the control ofM. aviumsubsp.paratuberculosis-specific T-cell responses.

scholarly journals Cooperation of PD-1 and LAG-3 Contributes to T-Cell Exhaustion in Anaplasma marginale-Infected Cattle

2016 ◽  
Vol 84 (10) ◽  
pp. 2779-2790 ◽  
Author(s):  
Tomohiro Okagawa ◽  
Satoru Konnai ◽  
James R. Deringer ◽  
Massaro W. Ueti ◽  
Glen A. Scoles ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Outer Membrane Proteins ◽  
T Cell Responses ◽  
Anaplasma Marginale ◽  
T Cell Exhaustion ◽  
Content Type ◽  
Cell Exhaustion ◽  
Cell Responses ◽  
Ifn Γ

The CD4+T-cell response is central for the control ofAnaplasma marginaleinfection in cattle. However, the infection induces a functional exhaustion of antigen-specific CD4+T cells in cattle immunized withA. marginaleouter membrane proteins or purified outer membranes (OMs), which presumably facilitates the persistence of this rickettsia. In the present study, we hypothesize that T-cell exhaustion following infection is induced by the upregulation of immunoinhibitory receptors on T cells, such as programmed death 1 (PD-1) and lymphocyte activation gene 3 (LAG-3). OM-specific T-cell responses and the kinetics of PD-1-positive (PD-1+) LAG-3+exhausted T cells were monitored inA. marginale-challenged cattle previously immunized with OMs. Consistent with data from previous studies, OM-specific proliferation of peripheral blood mononuclear cells (PBMCs) and interferon gamma (IFN-γ) production were significantly suppressed in challenged animals by 5 weeks postinfection (wpi). In addition, bacteremia and anemia also peaked in these animals at 5 wpi. Flow cytometric analysis revealed that the percentage of PD-1+LAG-3+T cells in the CD4+, CD8+, and γδ T-cell populations gradually increased and also peaked at 5 wpi. A large increase in the percentage of LAG-3+γδ T cells was also observed. Importantly,in vitro, the combined blockade of the PD-1 and LAG-3 pathways partially restored OM-specific PBMC proliferation and IFN-γ production at 5 wpi. Taken together, these results indicate that coexpression of PD-1 and LAG-3 on T cells contributes to the rapid exhaustion ofA. marginale-specific T cells following infection and that these immunoinhibitory receptors regulate T-cell responses during bovine anaplasmosis.

scholarly journals Transcription Factor IRF4 Promotes CD8+ T Cell Exhaustion and Limits the Development of Memory-like T Cells during Chronic Infection

Immunity ◽  
2017 ◽  
Vol 47 (6) ◽  
pp. 1129-1141.e5 ◽  
Author(s):  
Kevin Man ◽  
Sarah S. Gabriel ◽  
Yang Liao ◽  
Renee Gloury ◽  
Simon Preston ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Chronic Infection ◽  
Cd8 T Cell ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

scholarly journals Tim-3 co-stimulation promotes short-lived effector T cells, restricts memory precursors, and is dispensable for T cell exhaustion

2018 ◽  
Vol 115 (10) ◽  
pp. 2455-2460 ◽  
Author(s):  
Lyndsay Avery ◽  
Jessica Filderman ◽  
Andrea L. Szymczak-Workman ◽  
Lawrence P. Kane
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Chronic Infection ◽  
Cell Activation ◽  
Effector T Cells ◽  
Mtor Signaling ◽  
T Cell Exhaustion ◽  
Inhibitory Protein ◽  
Cell Exhaustion

Tim-3 is highly expressed on a subset of T cells during T cell exhaustion in settings of chronic viral infection and tumors. Using lymphocytic choriomeningitis virus (LCMV) Clone 13, a model for chronic infection, we found that Tim-3 was neither necessary nor sufficient for the development of T cell exhaustion. Nonetheless, expression of Tim-3 was sufficient to drive resistance to PD-L1 blockade therapy during chronic infection. Strikingly, expression of Tim-3 promoted the development of short-lived effector T cells, at the expense of memory precursor development, after acute LCMV infection. These effects were accompanied by increased Akt/mTOR signaling in T cells expressing endogenous or ectopic Tim-3. Conversely, Akt/mTOR signaling was reduced in effector T cells from Tim-3–deficient mice. Thus, Tim-3 is essential for optimal effector T cell responses, and may also contribute to exhaustion by restricting the development of long-lived memory T cells. Taken together, our results suggest that Tim-3 is actually more similar to costimulatory receptors that are up-regulated after T cell activation than to a dominant inhibitory protein like PD-1. These findings have significant implications for the development of anti–Tim-3 antibodies as therapeutic agents.

scholarly journals Gamma Interferon Is Required for Chlamydia Clearance but Is Dispensable for T Cell Homing to the Genital Tract

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Jennifer D. Helble ◽  
Rodrigo J. Gonzalez ◽  
Ulrich H. von Andrian ◽  
Michael N. Starnbach
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Chlamydia Trachomatis ◽  
Genital Tract ◽  
Gamma Interferon ◽  
Cell Homing ◽  
Content Type ◽  
T Cell Homing ◽  
Ifn Γ

ABSTRACT While there is no effective vaccine against Chlamydia trachomatis infection, previous work has demonstrated the importance of C. trachomatis-specific CD4+ T cells (NR1 T cells) in pathogen clearance. Specifically, NR1 T cells have been shown to be protective in mice, and this protection depends on the host’s ability to sense the cytokine gamma interferon (IFN-γ). However, it is unclear what role NR1 production or sensing of IFN-γ plays in T cell homing to the genital tract or T cell-mediated protection against C. trachomatis. Using two-photon microscopy and flow cytometry, we found that naive wild-type (WT), IFN-γ−/−, and IFN-γR−/− NR1 T cells specifically home to sections in the genital tract that contain C. trachomatis. We also determined that protection against infection requires production of IFN-γ from either NR1 T cells or endogenous cells, further highlighting the importance of IFN-γ in clearing C. trachomatis infection. IMPORTANCE Chlamydia trachomatis is an important mucosal pathogen that is the leading cause of sexually transmitted bacterial infections in the United States. Despite this, there is no vaccine currently available. In order to develop such a vaccine, it is necessary to understand the components of the immune response that can lead to protection against this pathogen. It is well known that antigen-specific CD4+ T cells are critical for Chlamydia clearance, but the contexts in which they are protective or not protective are unknown. Here, we aimed to characterize the importance of gamma interferon production and sensing by T cells and the effects on the immune response to C. trachomatis. Our work here helps to define the contexts in which antigen-specific T cells can be protective, which is critical to our ability to design an effective and protective vaccine against C. trachomatis.

scholarly journals Low Levels of T Cell Exhaustion in Tuberculous Lung Granulomas

2018 ◽  
Vol 86 (9) ◽  
Author(s):  
Eileen A. Wong ◽  
Louis Joslyn ◽  
Nicole L. Grant ◽  
Edwin Klein ◽  
Philana Ling Lin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cells ◽  
Cell Function ◽  
Cell Activity ◽  
Intrinsic Property ◽  
T Cell Exhaustion ◽  
Inhibitory Receptors ◽  
Content Type ◽  
Cell Exhaustion

ABSTRACTThe hallmarks of pulmonaryMycobacterium tuberculosisinfection are lung granulomas. These organized structures are composed of host immune cells whose purpose is to contain or clear infection, creating a complex hub of immune and bacterial cell activity, as well as limiting pathology in the lungs. Yet, given cellular activity and the potential for frequent interactions between host immune cells andM. tuberculosis-infected cells, we observed a surprisingly low quantity of cytokine-producing T cells (<10% of granuloma T cells) in our recent study ofM. tuberculosisinfection within nonhuman primate (NHP) granulomas. Various mechanisms could limit T cell function, and one hypothesis is T cell exhaustion. T cell exhaustion is proposed to result from continual antigen stimulation, inducing them to enter a state characterized by low cytokine production, low proliferation, and expression of a series of inhibitory receptors, the most common being PD-1, LAG-3, and CTLA-4. In this work, we characterized the expression of inhibitory receptors on T cells and the functionality of these cells in tuberculosis (TB) lung granulomas. We then used these experimental data to calibrate and inform an agent-based computational model that captures environmental, cellular, and bacterial dynamics within granulomas in lungs duringM. tuberculosisinfection. Together, the results of the modeling and the experimental work suggest that T cell exhaustion alone is not responsible for the low quantity ofM. tuberculosis-responsive T cells observed within TB granulomas and that the lack of exhaustion is likely an intrinsic property of granuloma structure.

scholarly journals The Transcription Factor NFAT1 Participates in the Induction of CD4+ T Cell Functional Exhaustion during Plasmodium yoelii Infection

2017 ◽  
Vol 85 (9) ◽  
Author(s):  
Rachel Y. Ames ◽  
Li-Min Ting ◽  
Inessa Gendlina ◽  
Kami Kim ◽  
Fernando Macian
Keyword(s):  
T Cells ◽  
T Cell ◽  
Acute Infection ◽  
Plasmodium Yoelii ◽  
T Cell Exhaustion ◽  
Wild Type ◽  
Content Type ◽  
Cell Exhaustion ◽  
Cognate Antigen ◽  
Effector Cytokines

ABSTRACT Repeated stimulation of T cells that occurs in the context of chronic infection results in progressively reduced responsiveness of T cells to pathogen-derived antigens. This phenotype, known as T cell exhaustion, occurs during chronic infections caused by a variety of pathogens, from persistent viruses to parasites. Unlike the memory cells that typically form after successful pathogen clearance following an acute infection, exhausted T cells secrete lower levels of effector cytokines, proliferate less in response to cognate antigen, and upregulate cell surface inhibitory molecules such as PD-1 and LAG-3. The molecular events that lead to the induction of this phenotype have, however, not been fully characterized. In T cells, members of the NFAT family of transcription factors not only are responsible for the expression of many activation-induced genes but also are crucial for the induction of transcriptional programs that inhibit T cell activation and maintain tolerance. Here we show that NFAT1-deficient CD4+ T cells maintain higher proliferative capacity and expression of effector cytokines following Plasmodium yoelii infection and are therefore more resistant to P. yoelii-induced exhaustion than their wild-type counterparts. Consequently, gene expression microarray analysis of CD4+ T cells following P. yoelii-induced exhaustion shows upregulation of effector T cell-associated genes in the absence of NFAT1 compared with wild-type exhausted T cells. Furthermore, adoptive transfer of NFAT1-deficient CD4+ T cells into mice infected with P. yoelii results in increased production of antibodies to cognate antigen. Our results support the idea that NFAT1 is necessary to fully suppress effector responses during Plasmodium-induced CD4+ T cell exhaustion.

scholarly journals T Cell-Independent Gamma Interferon and B Cells Cooperate To Prevent Mortality Associated with DisseminatedChlamydia muridarumGenital Tract Infection

2018 ◽  
Vol 86 (7) ◽  
pp. e00143-18 ◽  
Author(s):  
Taylor B. Poston ◽  
Catherine M. O'Connell ◽  
Jenna Girardi ◽  
Jeanne E. Sullivan ◽  
Uma M. Nagarajan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Tract Infection ◽  
B Cell ◽  
Gamma Interferon ◽  
Wild Type ◽  
Content Type ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACTCD4 T cells and antibody are required for optimal acquired immunity toChlamydia muridarumgenital tract infection, and T cell-mediated gamma interferon (IFN-γ) production is necessary to clear infection in the absence of humoral immunity. However, the role of T cell-independent immune responses during primary infection remains unclear. We investigated this question by inoculating wild-type and immune-deficient mice withC. muridarumCM001, a clonal isolate capable of enhanced extragenital replication. Genital inoculation of wild-type mice resulted in transient dissemination to the lungs and spleen that then was rapidly cleared from these organs. However, CM001 genital infection proved lethal forSTAT1−/−andIFNG−/−mice, in which IFN-γ signaling was absent, and forRag1−/−mice, which lacked T and B cells and in which innate IFN-γ signaling was retained. In contrast, B cell-deficient muMT mice, which can generate a Th1 response, and T cell-deficient mice with intact B cell and innate IFN-γ signaling survived. These data collectively indicate that IFN-γ prevents lethal CM001 dissemination in the absence of T cells and suggests a B cell corequirement. Adoptive transfer of convalescent-phase immune serum but not naive IgM toRag1−/−mice infected with CM001 significantly increased the survival time, while transfer of naive B cells completely rescuedRag1−/−mice from CM001 lethality. Protection was associated with a significant reduction in the lung chlamydial burden of genitally infected mice. These data reveal an important cooperation between T cell-independent B cell responses and innate IFN-γ in chlamydial host defense and suggest that interactions between T cell-independent antibody and IFN-γ are essential for limiting extragenital dissemination.

The Exhausted Intratumoral T Cell Population in B-Cell Non-Hodgkin Lymphoma Is Defined By LAG-3, PD-1 andtim-3 Expression

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2661-2661 ◽  
Author(s):  
Zhi-Zhang Yang ◽  
Tammy Price-troska ◽  
Anne J Novak ◽  
Stephen M Ansell
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cd8 T Cells ◽  
Conflicts Of Interest ◽  
Early Time ◽  
Effector Memory ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Ifn Γ

Abstract T-cell exhaustion plays an important role in attenuating the function of immune cells in B-cell non-Hodgkin's lymphoma (NHL) and PD-1 expression is typically used to identify exhausted T-cells. We have however previously shown that not all PD-1+ cells are exhausted and that PD-1 is differentially expressed on two distinct T-cell subpopulations, with high expression on T follicular helper cells and dim expression on exhausted T cells. Other markers are therefore needed to more clearly identify exhausted intratumoral T cells. To further define exhaustion of intratumoral T cells, we determined the co-expression, regulation and function of PD-1, TIM-3 and LAG-3 on CD4+ or CD8+ T cells by flow cytometry. Using biopsy specimens from follicular B-cell NHL, we found that the percentages of PD-1+ and TIM-3+ T cells were 53.1% (range: 17.2-81.2%, n=32) and 34.5% (range: 14.9-62.6%, n=34) in CD4+ T cells and 46.8% (range: 12.8-81.7%, n=32) and 40.4% (range: 15.0-78.4%, n=34) in CD8+ T cells, respectively. We observed that TIM-3 was predominantly expressed on PD-1dim T cells and TIM-3+ cells accounted for 40% of CD4+ PD-1dim or 45% of CD8+ PD-1dim T cells. Similarly, LAG-3 was variably expressed on intratumoral T cells from B-cell NHL. A median of 9.54% (range: 3.01-15.46, n=6) of CD4+ or 20.48% (7.93-33.9, n=8) of CD8+ T cells express LAG-3. We found that LAG-3+ T cells almost exclusively came from PD-1+ TIM-3+ cells, forming a defined population of intratumoral PD-1+ TIM-3+ LAG-3+ CD4+ or CD8+ T cells. While the majority of LAG-3+ T cells were effector memory T cells (CD45RA- CCR7-), some LAG-3-expressing T cells displayed a phenotype of terminally-differentiated T cells (CD45RA+ CCR7-). Functionally, the intratumoral TIM-3+ LAG-3+ T cells exhibited reduced capacity to produce cytokines (IL-2, IFN-γ) and granules (perforin, granzyme B). Similar to TIM-3, LAG-3 expression was strongly up-regulated on CD4+ or CD8+ T cells by IL-12, a cytokine that has been shown to induce T-cell exhaustion. Interestingly, we observed that while expression of TIM-3 on CD8+ T cells was upregulated by IL-12 at an early time point (day 1), LAG-3 was only induced after TIM-3 up-regulation (day 3) and almost exclusively on TIM-3+ T cells. Furthermore, we found that blockade of both TIM-3 and LAG-3 signaling was able to reverse the exhausted phenotype of CD8+ T cells resulting in increased IFN-γ and IL-2 production. This effect was further enhanced when CD8+ T cells were treated with both anti-TIM-3 and anti-LAG-3 Abs. Taken together, these results suggest that PD-1, TIM-3 and LAG-3 were involved in the induction of exhaustion of T cells in B-cell NHL. We find that PD-1, TIM-3 and LAG-3 are expressed on the same T cells and that blocking TIM-3 and LAG-3 can reverse T-cell exhaustion signaling. These results suggest that PD-1, TIM-3 and LAG-3 play a synergistic role in the development of T cell exhaustion in NHL. Disclosures No relevant conflicts of interest to declare.

scholarly journals Type 17 immunity promotes the exhaustion of CD8+ T cells in cancer

2021 ◽  
Vol 9 (6) ◽  
pp. e002603
Author(s):  
Byung-Seok Kim ◽  
Da-Sol Kuen ◽  
Choong-Hyun Koh ◽  
Hyung-Don Kim ◽  
Seon Hee Chang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Progression ◽  
Adoptive Transfer ◽  
Human Cancer ◽  
Strong Positive Correlation ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Tc17 Cells

BackgroundMultiple types of immune cells producing IL-17 are found in the tumor microenvironment. However, their roles in tumor progression and exhaustion of CD8+ tumor-infiltrating lymphocytes (TILs) remain unclear.MethodsTo determine the role of type 17 immunity in tumor, we investigated the growth of B16F10 melanoma and the exhaustion of CD8+ TILs in Il17a−/− mice, Il17aCreR26DTA mice, RORγt inhibitor-treated mice, or their respective control mice. Adoptive transfer of tumor-specific IL-17-producing T cells was performed in B16F10-bearing congenic mice. Anti-CD4 or anti-Ly6G antibodies were used to deplete CD4+ T cells or CD11b+Gr-1hi myeloid cells in vivo, respectively. Correlation between type 17 immunity and T cell exhaustion in human cancer was evaluated by interrogating TCGA dataset.ResultsDepletion of CD4+ T cells promotes the exhaustion of CD8+ T cells with a concomitant increase in IL-17-producing CD8+ T (Tc17) cells in the tumor. Unlike IFN-γ-producing CD8+ T (Tc1) cells, tumor-infiltrating Tc17 cells exhibit CD103+KLRG1−IL-7Rαhi tissue resident memory-like phenotypes and are poorly cytolytic. Adoptive transfer of IL-17-producing tumor-specific T cells increases, while depletion of IL-17-producing cells decreases, the frequency of PD-1hiTim3+TOX+ terminally exhausted CD8+ T cells in the tumor. Blockade of IL-17 or RORγt pathway inhibits exhaustion of CD8+ T cells and also delays tumor growth in vivo. Consistent with these results, human TCGA analyses reveal a strong positive correlation between type 17 and CD8+ T cell exhaustion signature gene sets in multiple cancers.ConclusionIL-17-producing cells promote terminal exhaustion of CD8+ T cells and tumor progression in vivo, which can be reversed by blockade of IL-17 or RORγt pathway. These findings unveil a novel role for IL-17-producing cells as tumor-promoting cells facilitating CD8+ T cell exhaustion, and propose type 17 immunity as a promising target for cancer immunotherapy.

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