scholarly journals IL-7 is essential for accumulation of antigen-specific CD8 T cells and to generate clonotype-specific effector responses during airway influenza/A infection

2021 ◽  
Author(s):  
Abdalla Sheikh ◽  
Jennie Jackson ◽  
Hanjoo Brian Shim ◽  
Clement Yau ◽  
Jung Hee Seo ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Mediastinal Lymph Node ◽  
Cd8 T Cell ◽  
Interleukin 7 ◽  
And Function ◽  
Deficient Mice

AbstractAirborne diseases are the leading cause of infectious disease-related deaths in the world. In particular, the influenza virus activates a network of immune cells that leads to clearance or an overzealous response that can be fatal. Tight regulation of the cytokines that enable proper activation and function of immune cells is necessary to clear infections efficiently while minimizing damage to the host. Interleukin-7 (IL-7) is a cytokine known for its importance in T cell development and survival. How IL-7 shapes CD8 T cell responses during an acute viral infection is less understood. We had previously shown that IL-7 signaling deficient mice have reduced accumulation of influenza-specific CD8 T cells following infection. We sought to determine whether IL-7 affects early CD8 T cell expansion in the mediastinal lymph node and effector function in the lungs. Using IL-7Rα signaling deficient mice, we show that IL-7 is required for a normal sized mediastinal lymph node and the early clonal expansion of antigen-specific CD8 T cells therein. Bone marrow chimeric models and adoptive transfer of transgenic TCR CD8 T cells reveal a cell-intrinsic role for IL-7 in the accumulation of NP366–374 and PA224–233-specific CD8 T cells. We also found that IL-7 dictates terminal differentiation, degranulation and cytokine production in PA224–233-specific but not NP366–374-specific CD8 T cells. We further demonstrate that IL-7 is induced in the lung tissue by viral infection and we characterize multiple cellular sources that contribute to IL-7 production. Drugs that manipulate IL-7 signaling are currently under clinical trial for multiple conditions. Our findings on IL-7 and its effects on lower respiratory diseases will be important for expanding the utility of these therapeutics.Author SummaryInterleukin-7 plays an important role in development of immune cells such as lymphocytes. In recent years, its role in the immune system has been expanded beyond the development of immune cells to include revitalizing of lymphocytes during tumor and chronic viral response. We show here that IL-7 is required for accumulation and function of specialized lymphocytes in the lungs during an acute influenza infection.

scholarly journals Selective dependence on IL-7 for antigen-specific CD8 T cell responses during airway influenza infection

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Abdalla Sheikh ◽  
Jennie Jackson ◽  
Hanjoo Brian Shim ◽  
Clement Yau ◽  
Jung Hee Seo ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
Mediastinal Lymph Node ◽  
Influenza Infection ◽  
Cd8 T Cell ◽  
Cell Responses ◽  
Deficient Mice

AbstractInterleukin-7 (IL-7) is a cytokine known for its importance in T cell development and survival. How IL-7 shapes CD8 T cell responses during an acute viral infection is less understood. We had previously shown that IL-7 signaling deficient mice have reduced accumulation of influenza-specific CD8 T cells following influenza infection. We sought to determine whether IL-7 affects early CD8 T cell expansion in the mediastinal lymph node and effector function in the lungs. Using IL-7Rα signaling deficient mice, we show that IL-7 is required for a normal sized mediastinal lymph node and the early clonal expansion of influenza-specific CD8 T cells therein. We show that IL-7 plays a cell-intrinsic role in the accumulation of NP366–374 and PA224–233-specific CD8 T cells in the lymph node. We also found that IL-7 shapes terminal differentiation, degranulation and cytokine production to a greater extent in PA224–233-specific than NP366–374-specific CD8 T cells. We further demonstrate that IL-7 is induced in the lung tissue by viral infection and we characterize multiple cellular sources that contribute to IL-7 production. Our findings on IL-7 and its effects on lower respiratory diseases will be important for expanding the utility of therapeutics that are currently available.

scholarly journals Direct and Indirect endocrine-mediated suppression of human endometrial CD8+T cell cytotoxicity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Z. Shen ◽  
M. Rodriguez-Garcia ◽  
M. V. Patel ◽  
C. R. Wira
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cytotoxic Activity ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Cd8 T Cell ◽  
Gynecological Cancers ◽  
Protective Strategies ◽  
T Cell Cytotoxicity

AbstractRegulation of endometrial (EM) CD8+T cells is essential for successful reproduction and protection against pathogens. Suppression of CD8+T cells is necessary for a tolerogenic environment that promotes implantation and pregnancy. However, the mechanisms regulating this process remain unclear. Sex hormones are known to control immune responses directly on immune cells and indirectly through the tissue environment. When the actions of estradiol (E2), progesterone (P) and TGFβ on EM CD8+T cells were evaluated, cytotoxic activity, perforin and granzymes were directly suppressed by E2 and TGFβ but not P. Moreover, incubation of polarized EM epithelial cells with P, but not E2, increased TGFβ secretion. These findings suggest that E2 acts directly on CD8+T cell to suppress cytotoxic activity while P acts indirectly through induction of TGFβ production. Understanding the mechanisms involved in regulating endometrial CD8+T cells is essential for optimizing reproductive success and developing protective strategies against genital infections and gynecological cancers.

scholarly journals Self–class I MHC molecules support survival of naive CD8 T cells, but depress their functional sensitivity through regulation of CD8 expression levels

2009 ◽  
Vol 206 (10) ◽  
pp. 2253-2269 ◽  
Author(s):  
Kensuke Takada ◽  
Stephen C. Jameson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Survival ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Class I ◽  
Class I Mhc ◽  
Mhc Molecules ◽  
T Cell Survival ◽  
And Function

Previous studies have suggested that naive CD8 T cells require self-peptide–major histocompatability complex (MHC) complexes for maintenance. However, interpretation of such studies is complicated because of the involvement of lymphopenic animals, as lymphopenia drastically alters naive T cell homeostasis and function. In this study, we explored naive CD8 T cell survival and function in nonlymphopenic conditions by using bone marrow chimeric donors and hosts in which class I MHC expression is absent or limited to radiosensitive versus radioresistant cells. We found that long-term survival of naive CD8 T cells (but not CD4 T cells) was impaired in the absence of class I MHC. However, distinct from this effect, class I MHC deprivation also enhanced naive CD8 T cell responsiveness to low-affinity (but not high-affinity) peptide–MHC ligands. We found that this improved sensitivity was a consequence of up-regulated CD8 levels, which was mediated through a transcriptional mechanism. Hence, our data suggest that, in a nonlymphopenic setting, self-class I MHC molecules support CD8 T cell survival, but that these interactions also attenuate naive T cell sensitivity by dynamic tuning of CD8 levels.

scholarly journals CD11a Regulates Effector CD8 T Cell Differentiation and Central Memory Development in Response to Infection with Listeria monocytogenes

2013 ◽  
Vol 81 (4) ◽  
pp. 1140-1151 ◽  
Author(s):  
Tina O. Bose ◽  
Quynh-Mai Pham ◽  
Evan R. Jellison ◽  
Juliette Mouries ◽  
Christie M. Ballantyne ◽  
...  
Keyword(s):  
T Cells ◽  
Listeria Monocytogenes ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Central Memory ◽  
Secondary Response ◽  
Cellular Interactions ◽  
Deficient Mice

ABSTRACTβ2 (CD18) integrins with α-chains CD11a, -b, -c, and -d are important adhesion molecules necessary for leukocyte migration and cellular interactions. CD18 deficiency leads to recurrent bacterial infections and poor wound healing due to reduced migration of leukocytes to inflammatory sites. CD8 T cells also upregulate CD11a, CD11b, and CD11c upon activation. However, the role these molecules play for CD8 T cellsin vivois not known. To determine the function of individual β2 integrins, we examined CD8 T cell responses toListeria monocytogenesinfection in CD11a-, CD11b-, and CD11c-deficient mice. The absence of CD11b or CD11c had no effect on the generation of antigen-specific CD8 T cells. In contrast, the magnitude of the primary CD8 T cell response in CD11a-deficient mice was significantly reduced. Moreover, the response in CD11a−/−mice exhibited reduced differentiation of short-lived effector cells (KLRG1hiCD127lo), although cytokine and granzyme B production levels were unaffected. Notably, CD11a deficiency resulted in greatly enhanced generation of CD62L+central memory cells. Surprisingly, CD8 T cells lacking CD11a mounted a robust secondary response to infection. Taken together, these findings demonstrated that CD11a expression contributes to expansion and differentiation of primary CD8 T cells but may be dispensable for secondary responses to infection.

scholarly journals CD8+ T Cells in GCA and GPA: Bystanders or Active Contributors?

2021 ◽  
Vol 12 ◽  
Author(s):  
Rosanne D. Reitsema ◽  
Annemieke M. H. Boots ◽  
Kornelis S. M. van der Geest ◽  
Maria Sandovici ◽  
Peter Heeringa ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Blood Vessels ◽  
Cd8 T Cells ◽  
Current Knowledge ◽  
Adaptive Immune Response ◽  
Cd8 T Cell ◽  
Cell Phenotype ◽  
Functional Features ◽  
And Function

Vasculitis refers to inflammation of blood vessels and can cause a variety of serious complications depending on which vessels are affected. Two different forms of vasculitis are Giant Cell Arteritis (GCA) and Granulomatosis with Polyangiitis (GPA). GCA is the most common form of vasculitis in adults affecting the large arteries and can lead to visual impairment and development of aneurysms. GPA affects small- and medium-sized blood vessels predominantly in the lungs and kidneys resulting in organ failure. Both diseases can potentially be fatal. Although the pathogenesis of GCA and GPA are incompletely understood, a prominent role for CD4+ T cells has been implicated in both diseases. More recently, the role of CD8+ T cells has gained renewed interest. CD8+ T cells are important players in the adaptive immune response against intracellular microorganisms. After a general introduction on the different forms of vasculitis and their association with infections and CD8+ T cells, we review the current knowledge on CD8+ T-cell involvement in the immunopathogenesis of GCA and GPA focusing on phenotypic and functional features of circulating and lesional CD8+ T cells. Furthermore, we discuss to which extent aging is associated with CD8+ T-cell phenotype and function in GCA and GPA.

scholarly journals Targeting Pim2 for Improving T-Cell Effector Function and Promoting Cancer Immunotherapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1720-1720
Author(s):  
Yongxia Wu ◽  
Linlu Tian ◽  
Corey Mealer ◽  
Hee-Jin Choi ◽  
Xue-Zhong Yu
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Effector Function ◽  
Cell Responses ◽  
Deficient Mice

Abstract The Provirus Integration sites for Moloney murine leukemia virus (Pim) kinases are a highly conserved family of serine/threonine kinases. The Pim kinase family is composed of three different isoforms, Pim1, Pim2, and Pim3, which have been studied extensively in tumorigenesis and as a potential therapeutic target in various cancers. We previously reported an unexpected role of Pim2 in negatively regulates T-cell responses to alloantigen and tumor (JCI, 2015, PMID: 29781812). However, the mechanisms by which Pim2 modulates T-cell responses remain largely undefined. In the current study, using genetic Pim2-deficient mouse, we demonstrated a key role of Pim2 in regulating T-cell hemostatic and anti-tumor responses in aging, hematopoietic cell transplantation (HCT), and antigen-specific adoptive T-cell therapy (ACT). We observed that Pim2 was critical for T cells to retain quiescent in aged mice, as thymic Treg development was impaired while effector T-cell differentiation in lymphoid organs, including Tc1/Th1, Tc17/Th17 and follicular helper T cells, was increased in Pim2-deficient mice, but not in Pim1/Pim3-deficient mice. Furthermore, Pim2-deficient mice were capable to completely eradicate syngeneic breast cancer (NT2.5) growth (Figure A). During antigen specific anti-tumor response, adoptively transferred Pim2 -/- CD8 T cells showed enhanced ability for controlling established NT2.5 breast cancer and B16 melanoma (Figure B, C). Mechanistically, loss of Pim2 promoted G1 to S phase cell-cycle progression while reduced apoptosis in CD8 T cells. Pim2 -/- CD8 T cells exhibited elevated effector cytokine production while maintained higher levels of CD62L expression, leading to superior effector function, persistence and anti-tumor activity. Reduced differentiation of exhausted and suppressive subsets were observed in Pim2 -/- CD8 T cells after being adoptively transferred in tumor-bearing mice. In addition, Pim2 deficiency was associated with a higher metabolic potential, reflected by increased glycolysis and oxidative phosphorylation, which was at least partially attributed to a decreased level of autophagy in Pim2 -/- CD8 T cells. To further evaluate the clinical translation potential, we applied a Pim2-specific inhibitor (JP11646) and found that blocking Pim2 improved graft-versus-leukemia activity after autologous HCT and also enhanced CD8 T-cell mediated anti-melanoma effects after ACT in mice (Figure B, C). Furthermore, blocking Pim2 using JP11646 promoted human CD8 T-cell response during polyclonal stimulation and enhanced expansion, effector function and tumor killing ability of human melanoma antigen-specific CD8 T cells (data not shown) and CD19 CAR-T cells (Figure D). Our work demonstrated that Pim2 is a potent and distinct regulator of differentiation and maintenance of T effector cells through modulating metabolism and autophagy. Specifically target Pim2 can serve as a novel strategy for improving cancer immunotherapy. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Loss of Bim Increases T Cell Production and Function in Interleukin 7 Receptor–deficient Mice

2004 ◽  
Vol 200 (9) ◽  
pp. 1189-1195 ◽  
Author(s):  
Marc Pellegrini ◽  
Philippe Bouillet ◽  
Mikara Robati ◽  
Gabrielle T. Belz ◽  
Gayle M. Davey ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytotoxic T Cell ◽  
Normal Numbers ◽  
Transgenic Expression ◽  
Interleukin 7 ◽  
Cytotoxic T Cell Responses ◽  
And Function ◽  
Deficient Mice

Interleukin (IL)-7 receptor (R) signaling is essential for T and B lymphopoiesis by promoting proliferation, differentiation, and survival of cells. Mice lacking either IL-7 or the IL-7Rα chain have abnormally low numbers of immature as well as mature T and B lymphocytes. Transgenic expression of the apoptosis inhibitor Bcl-2 rescues T cell development and function in IL-7Rα–deficient mice, indicating that activation of a proapoptotic Bcl-2 family member causes death of immature and mature T cells. BH3-only proteins such as Bim, which are distant proapoptotic members of the Bcl-2 family, are essential initiators of programmed cell death and stress-induced apoptosis. We generated Bim/IL-7Rα double deficient mice and found that loss of Bim significantly increased thymocyte numbers, restored near normal numbers of mature T cells in the blood and spleen, and enhanced cytotoxic T cell responses to virus infection in IL-7Rα−/− mice. These results indicate that Bim cooperates with other proapoptotic proteins in the death of IL-7–deprived T cell progenitors in vivo, but is the major inducer of this pathway to apoptosis in mature T cells. This indicates that pharmacological inhibition of Bim function might be useful for boosting immune responses in immunodeficient patients.

Analysis of the Fate and Function of Antigen-Specific CD8 T Cells during B Cell Lymphoma Progression.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 80-80 ◽  
Author(s):  
Jason Brayer ◽  
Fengdong Cheng ◽  
Pedro Horna ◽  
Ildefonso Suarez ◽  
Hongwei Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
B Cell Lymphoma ◽  
Cd8 T Cell ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
Stat3 Signaling ◽  
And Function

Abstract There is now overwhelming evidence that tumor-induced antigen (Ag)-specific T cell tolerance represents a critical problem in tumor immunology. Early studies of CD8 T cell tolerance equated peripheral tolerance with either ignorance or clonal deletion, although more recent evidence has suggested that this may be only partly accurate. While murine modeling outwardly supports the contention that high-affinity tumor-specific CD8 T cell responses are centrally deleted, cognate CD8 T cells displaying an Ag-experienced phenotype can nonetheless be detected in regional draining lymph nodes (dLN) or in non-lymphoid sites where the Ag is present. However, these CD8 T cells are typically deficient in one or more effector functions, including cytokine production, cytotoxicity, or proliferative capacity. To better define the state of Ag-specific CD8 T cell responsiveness in the face of progressive tumor, we adoptively transferred hemagglutinin (HA) Ag-specific Clone 4 (CLN4) CD8 T cells into animals bearing a genetically modified B cell lymphoma expressing HA as a model tumor antigen (A20HA). Analysis of the fate and function of these transferred antigen-specific CD8 T cells revealed that they encountered antigen in vivo, were capable of mounting an initial response to A20HA but this response was not sustained. Indeed, while a prominent CTL activation was observed in the spleen and draining lymph nodes of tumor bearing mice within 14 days of T cell transfer, responses (HA-specific proliferation, IFN-γ production and cytotoxicity) began to wane by day 21 after T cell transfer, and in particular their ability to produce IFN-γ. A similar pattern of transient activation followed by loss of CD8 T cell function has been also observed in an in vivo model of high-dose peptide induced antigen-specific CD8 T cell tolerance. Given our recent demonstration that the disruption of Stat3 signaling in APCs overcomes CD4 T cell tolerance we determined next whether Stat3 deficient APCs may be inherently better at cross-presenting tumor-Ags and elicit therefore a more productive and sustained CD8 T cell response. In an in vitro system in which tumor cells expressing a model tumor antigen (EL4mOVA) were cultured with APCs genetically devoid of Stat3 signaling and anti-OVA CD8 T-cells (OT-I), we found that these T cells displayed an enhanced function relative to antigen-specific CD8 T-cells that encountered antigen on APCs with an intact Stat3 signaling. Currently, we are investigating whether CD8 T-cell tolerance to tumor antigens occurred -or not- in tumor bearing mice with a genetic disruption of Stat3 signaling in APCs. Furthermore, given the emerging role of other members of the STAT family in regulation of APC function, we are exploring whether targeted disruption of Stat1, 4 and 6 can alter the ability of the CD8 T-cell to sustain a protective response or, more importantly to recover function once tolerance is induced.

scholarly journals Antiviral memory CD8 T-cell differentiation, maintenance, and secondary expansion occur independently of MyD88

Blood ◽  
2011 ◽  
Vol 117 (11) ◽  
pp. 3123-3130 ◽  
Author(s):  
Adeeb H. Rahman ◽  
Ruan Zhang ◽  
Christopher D. Blosser ◽  
Baidong Hou ◽  
Anthony L. DeFranco ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Cell Expansion ◽  
Cd8 T Cell ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Memory Cd8 T Cells ◽  
T Cell Expansion

Abstract Inflammatory signals induced during infection regulate T-cell expansion, differentiation, and memory formation. Toll-like receptors (TLRs) are inflammatory mediators that allow innate immune cells to recognize and respond to invading pathogens. In addition to their role in innate immune cells, we have found that signals delivered through the TLR adapter protein myeloid differentiation protein 88 (MyD88) play a critical, T cell–intrinsic role in supporting the survival and accumulation of antigen-specific effector cells after acute viral infection. However, the importance of MyD88-dependent signals in regulating the generation and maintenance of memory T cells remained unclear. To address this, we used a novel, inducible knockout system to examine whether MyD88 is required for optimal memory CD8 T-cell generation and responses after lymphocytic choriomeningitis virus infection. We show that whereas MyD88 is critical for initial T-cell expansion, it is not required for the subsequent differentiation and stable maintenance of a memory T-cell population. Furthermore, in contrast to naive CD8 T cells, memory CD8 T cells do not depend on MyD88 for their secondary expansion. Our findings clarify the importance of MyD88 during distinct phases of the antiviral T-cell response and establish differential dependence on MyD88 signaling as a novel characteristic that distinguishes naive from memory CD8 T cells.

scholarly journals The DARC-null trait is associated with moderate modulation of NK cell profiles and unaltered cytolytic T cell profiles in black South Africans

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0242448
Author(s):  
Kewreshini K. Naidoo ◽  
Zesuliwe B. Shangase ◽  
Tabassum Rashid ◽  
Ayanda Ngubane ◽  
Nasreen Ismail ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Full Blood Count ◽  
Cell Counts ◽  
Hiv 1

The Duffy Antigen Receptor for Chemokines (DARC)-null trait, common among persons of African descent and associated with lower absolute neutrophil counts (ANCs), may be linked to increased risk to certain infections including HIV-1 but the underlying causes are poorly understood. We hypothesized that DARC-null-linked neutropenia may negatively impact neutrophil immunoregulatory modulation of other immune cells such as natural killer (NK) and CD8+ T cells leading to altered phenotype, functionality and homeostatic activity of these immune cells. HIV-1 uninfected (n = 20) and HIV-1 chronically infected (n = 19) participants were assessed using multi-parametric flow cytometry to determine NK and CD8+ T cell counts, phenotypic profiles, and cytokine production and degranulation. Annexin V and carboxyfluorescein succinimidyl ester (CFSE) staining were used to examine NK cell survival and NK cell and CD8+ T cell proliferation respectively. Participants were genotyped for the DARC-null polymorphism using allelic discrimination assays and ANCs were measured by full blood count. In HIV uninfected individuals, a reduction of total NK cell counts was noted in the absence of DARC and this correlated with lower ANCs. HIV uninfected DARC-null subjects displayed a less mature NK cell phenotype. However, this did not translate to differences in NK cell activation or effector functionality by DARC state. Whilst HIV-1 infected subjects displayed NK cell profiling that is typical of HIV infection, no differences were noted upon DARC stratification. Similarly, CD8+ T cells from HIV infected individuals displayed phenotypic and functional modulation that is characteristic of HIV infection, but profiling was unaffected by the DARC-null variant irrespective of HIV status. Overall, the data suggests that the DARC-null polymorphism and lower ANCs does not impede downstream cytolytic cell priming and functionality.

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