scholarly journals DOCK8 deficiency impairs CD8 T cell survival and function in humans and mice

2011 ◽  
Vol 208 (11) ◽  
pp. 2305-2320 ◽  
Author(s):  
Katrina L. Randall ◽  
Stephanie S.-Y. Chan ◽  
Cindy S. Ma ◽  
Ivan Fung ◽  
Yan Mei ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Survival ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Viral Infections ◽  
Cd8 T Cell ◽  
T Cell Survival ◽  
And Function

In humans, DOCK8 immunodeficiency syndrome is characterized by severe cutaneous viral infections. Thus, CD8 T cell function may be compromised in the absence of DOCK8. In this study, by analyzing mutant mice and humans, we demonstrate a critical, intrinsic role for DOCK8 in peripheral CD8 T cell survival and function. DOCK8 mutation selectively diminished the abundance of circulating naive CD8 T cells in both species, and in DOCK8-deficient humans, most CD8 T cells displayed an exhausted CD45RA+CCR7− phenotype. Analyses in mice revealed the CD8 T cell abnormalities to be cell autonomous and primarily postthymic. DOCK8 mutant naive CD8 T cells had a shorter lifespan and, upon encounter with antigen on dendritic cells, exhibited poor LFA-1 synaptic polarization and a delay in the first cell division. Although DOCK8 mutant T cells underwent near-normal primary clonal expansion after primary infection with recombinant influenza virus in vivo, they showed greatly reduced memory cell persistence and recall. These findings highlight a key role for DOCK8 in the survival and function of human and mouse CD8 T cells.

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 Combined Deficiency of p50 and cRel in CD4+ T Cells Reveals an Essential Requirement for Nuclear Factor κB in Regulating Mature T Cell Survival and In Vivo Function

2003 ◽  
Vol 197 (7) ◽  
pp. 861-874 ◽  
Author(s):  
Ye Zheng ◽  
Monika Vig ◽  
Jesse Lyons ◽  
Luk Van Parijs ◽  
Amer A. Beg
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Survival ◽  
Cd4 T Cells ◽  
Cell Function ◽  
Nuclear Factor ◽  
T Cell Function ◽  
T Cell Survival

Signaling pathways involved in regulating T cell proliferation and survival are not well understood. Here we have investigated a possible role of the nuclear factor (NF)-κB pathway in regulating mature T cell function by using CD4+ T cells from p50−/− cRel−/− mice, which exhibit virtually no inducible κB site binding activity. Studies with these mice indicate an essential role of T cell receptor (TCR)-induced NF-κB in regulating interleukin (IL)-2 expression, cell cycle entry, and survival of T cells. Our results further indicate that NF-κB regulates TCR-induced expression of antiapoptotic Bcl-2 family members. Strikingly, retroviral transduction of CD4+ T cells with the NF-κB–inducing IκB kinase β showed that NF-κB activation is not only necessary but also sufficient for T cell survival. In contrast, our results indicate a lack of involvement of NF-κB in both IL-2 and Akt-induced survival pathways. In vivo, p50−/− cRel−/− mice showed impaired superantigen-induced T cell responses as well as decreased numbers of effector/memory and regulatory CD4+ T cells. These findings provide the first demonstration of a role for NF-κB proteins in regulating T cell function in vivo and establish a critically important function of NF-κB in TCR-induced regulation of survival.

scholarly journals Exhausted CD8+ T cells exhibit low and strongly inhibited TCR signaling during chronic LCMV infection

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Ioana Sandu ◽  
Dario Cerletti ◽  
Manfred Claassen ◽  
Annette Oxenius
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Viral Infections ◽  
Cell Receptor ◽  
Target Cells ◽  
Tcr Signaling ◽  
And Function

Abstract Chronic viral infections are often associated with impaired CD8+ T cell function, referred to as exhaustion. Although the molecular and cellular circuits involved in CD8+ T cell exhaustion are well defined, with sustained presence of antigen being one important parameter, how much T cell receptor (TCR) signaling is actually ongoing in vivo during established chronic infection is unclear. Here, we characterize the in vivo TCR signaling of virus-specific exhausted CD8+ T cells in a mouse model, leveraging TCR signaling reporter mice in combination with transcriptomics. In vivo signaling in exhausted cells is low, in contrast to their in vitro signaling potential, and despite antigen being abundantly present. Both checkpoint blockade and adoptive transfer of naïve target cells increase TCR signaling, demonstrating that engagement of co-inhibitory receptors curtails CD8+ T cell signaling and function in vivo.

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 IL-15 trans-presentation by pulmonary dendritic cells promotes effector CD8 T cell survival during influenza virus infection

2010 ◽  
Vol 207 (3) ◽  
pp. 521-534 ◽  
Author(s):  
Jodi McGill ◽  
Nico Van Rooijen ◽  
Kevin L. Legge
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Virus Infection ◽  
Cell Survival ◽  
Cd8 T Cells ◽  
Influenza Virus Infection ◽  
Cd8 T Cell ◽  
T Cell Survival

We have recently demonstrated that peripheral CD8 T cells require two separate activation hits to accumulate to high numbers in the lungs after influenza virus infection: a primary interaction with mature, antigen-bearing dendritic cells (DCs) in the lymph node, and a second, previously unrecognized interaction with MHC I–viral antigen–bearing pulmonary DCs in the lungs. We demonstrate that in the absence of lung-resident DC subsets, virus-specific CD8 T cells undergo significantly increased levels of apoptosis in the lungs; however, reconstitution with pulmonary plasmacytoid DCs and CD8α+ DCs promotes increased T cell survival and accumulation in the lungs. Further, our results show that the absence of DCs after influenza virus infection results in significantly reduced levels of IL-15 in the lungs and that pulmonary DC–mediated rescue of virus-specific CD8 T cell responses in the lungs requires trans-presentation of IL-15 via DC-expressed IL-15Rα. This study demonstrates a key, novel requirement for DC trans-presented IL-15 in promoting effector CD8 T cell survival in the respiratory tract after virus infection, and suggests that this trans-presentation could be an important target for the development of unique antiviral therapies and more effective vaccine strategies.

scholarly journals IL-17RA-signaling modulates CD8+ T cell survival and exhaustion during Trypanosoma cruzi infection

2018 ◽  
Author(s):  
Jimena Tosello Boari ◽  
Cintia L. Araujo Furlan ◽  
Facundo Fiocca Vernengo ◽  
Constanza Rodriguez ◽  
María C. Ramello ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Trypanosoma Cruzi ◽  
Cell Survival ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
T Cell Immunity ◽  
Cell Immunity ◽  
T Cell Survival

AbstractThe IL-17 family contributes to host defense against many intracellular pathogens by mechanisms not fully understood. CD8+ T lymphocytes are key elements against intracellular microbes and their survival and appropriate response is orchestrated by several cytokines. Here, we demonstrated that IL-17RA-signaling cytokines sustain pathogen-specific CD8+ T cell immunity. Absence of IL-17RA and IL-17A/F during Trypanosoma cruzi infection resulted in increased tissue parasitism and reduced frequency of parasite-specific CD8+ T cells. Impaired IL-17RA-signaling in vivo increased apoptosis of parasite-specific CD8+ T cells while recombinant IL-17 in vitro down-regulated the pro-apoptotic protein BAD and promoted activated CD8+ T cell survival. Phenotypic, functional and trancriptomic profiling showed that T. cruzi-specific CD8+ T cells arising in IL-17RA-deficient mice presented features of cell dysfunction. PD-L1 blockade partially restored the magnitude of CD8+ T cell responses and parasite control in these mice. Adoptive transfer experiments established that IL-17RA-signaling is intrinsically required for the proper maintenance of functional effector CD8+ T cells. Altogether, our results identify IL-17RA and IL-17A as critical factors for sustaining CD8+ T cell immunity to T. cruzi.

scholarly journals DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors

2008 ◽  
Vol 205 (13) ◽  
pp. 2965-2973 ◽  
Author(s):  
Susan Gilfillan ◽  
Christopher J. Chan ◽  
Marina Cella ◽  
Nicole M. Haynes ◽  
Aaron S. Rapaport ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Adhesion Molecules ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Antigen Presenting

Natural killer (NK) cells and CD8 T cells require adhesion molecules for migration, activation, expansion, differentiation, and effector functions. DNAX accessory molecule 1 (DNAM-1), an adhesion molecule belonging to the immunoglobulin superfamily, promotes many of these functions in vitro. However, because NK cells and CD8 T cells express multiple adhesion molecules, it is unclear whether DNAM-1 has a unique function or is effectively redundant in vivo. To address this question, we generated mice lacking DNAM-1 and evaluated DNAM-1–deficient CD8 T cell and NK cell function in vitro and in vivo. Our results demonstrate that CD8 T cells require DNAM-1 for co-stimulation when recognizing antigen presented by nonprofessional antigen-presenting cells; in contrast, DNAM-1 is dispensable when dendritic cells present the antigen. Similarly, NK cells require DNAM-1 for the elimination of tumor cells that are comparatively resistant to NK cell–mediated cytotoxicity caused by the paucity of other NK cell–activating ligands. We conclude that DNAM-1 serves to extend the range of target cells that can activate CD8 T cell and NK cells and, hence, may be essential for immunosurveillance against tumors and/or viruses that evade recognition by other activating or accessory molecules.

scholarly journals Role of Thymic Output in Regulating CD8 T-Cell Homeostasis during Acute and Chronic Viral Infection

2005 ◽  
Vol 79 (15) ◽  
pp. 9419-9429 ◽  
Author(s):  
Nicole E. Miller ◽  
Jennifer R. Bonczyk ◽  
Yumi Nakayama ◽  
M. Suresh
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Viral Infections ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cell Responses ◽  
Lcmv Infection

ABSTRACT Although it is well documented that CD8 T cells play a critical role in controlling chronic viral infections, the mechanisms underlying the regulation of CD8 T-cell responses are not well understood. Using the mouse model of an acute and chronic lymphocytic choriomeningitis virus (LCMV) infection, we have examined the relative importance of peripheral T cells and thymic emigrants in the elicitation and maintenance of CD8 T-cell responses. Virus-specific CD8 T-cell responses were compared between mice that were either sham thymectomized or thymectomized (Thx) at ∼6 weeks of age. In an acute LCMV infection, thymic deficiency did not affect either the primary expansion of CD8 T cells or the proliferative renewal and maintenance of virus-specific lymphoid and nonlymphoid memory CD8 T cells. Following a chronic LCMV infection, in Thx mice, although the initial expansion of CD8 T cells was normal, the contraction phase of the CD8 T-cell response was exaggerated, which led to a transient but striking CD8 T-cell deficit on day 30 postinfection. However, the virus-specific CD8 T-cell response in Thx mice rebounded quickly and was maintained at normal levels thereafter, which indicated that the peripheral T-cell repertoire is quite robust and capable of sustaining an effective CD8 T-cell response in the absence of thymic output during a chronic LCMV infection. Taken together, these findings should further our understanding of the regulation of CD8 T-cell homeostasis in acute and chronic viral infections and might have implications in the development of immunotherapy.

scholarly journals CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance

2009 ◽  
Vol 206 (2) ◽  
pp. 421-434 ◽  
Author(s):  
Randall H. Friedline ◽  
David S. Brown ◽  
Hai Nguyen ◽  
Hardy Kornfeld ◽  
JinHee Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Function ◽  
Cytotoxic T Lymphocyte ◽  
Critical Role ◽  
Lymphoproliferative Disease ◽  
In Trans ◽  
And Function

Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a critical role in negatively regulating T cell responses and has also been implicated in the development and function of natural FOXP3+ regulatory T cells. CTLA-4–deficient mice develop fatal, early onset lymphoproliferative disease. However, chimeric mice containing both CTLA-4–deficient and –sufficient bone marrow (BM)–derived cells do not develop disease, indicating that CTLA-4 can act in trans to maintain T cell self-tolerance. Using genetically mixed blastocyst and BM chimaeras as well as in vivo T cell transfer systems, we demonstrate that in vivo regulation of Ctla4−/− T cells in trans by CTLA-4–sufficient T cells is a reversible process that requires the persistent presence of FOXP3+ regulatory T cells with a diverse TCR repertoire. Based on gene expression studies, the regulatory T cells do not appear to act directly on T cells, suggesting they may instead modulate the stimulatory activities of antigen-presenting cells. These results demonstrate that CTLA-4 is absolutely required for FOXP3+ regulatory T cell function in vivo.

scholarly journals Serum-derived exosomes promote CD8+ T cells to overexpress PD-1, affecting the prognosis of hypopharyngeal carcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Qian Gao ◽  
Hui-Ting Liu ◽  
Yu-Qin Xu ◽  
Lin Zhang ◽  
Yuan-Ru Liu ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
Cd8 T Cells ◽  
Poor Prognosis ◽  
Cell Function ◽  
Immune Escape ◽  
Cd8 T Cell ◽  
Serum Exosomes

Abstract Background Hypopharyngeal cancer (HPC) is associated with a poor prognosis and a high recurrence rate. Immune escape is one of the reasons for the poor prognosis of malignant tumors. Programmed cell death ligand 1 (PD-L1) and programmed cell death-1 (PD-1) have been shown to play important roles in immune escape. However, the role of PD-1/PD-L1 in HPC remains unclear. In this experiment, we investigated the effect of exosomes from HPC patient serum on CD8+ T cell function and PD-1/PD-L1 expression and, thus, on prognosis. We hope to provide guidance for the identification of new targets for HPC immunotherapy. Methods PD-1 and CD8 expression in 71 HPC tissues and 16 paracarcinoma tissues was detected by immunohistochemistry. Concurrently, the clinicopathological data of the patients were obtained to conduct correlation analysis. Exosomes were isolated from serum and then identified by Western blotting (WB), transmission electron microscopy (TEM), and nanoparticle tracking analysis (NTA). Flow cytometry was used to assess the activity of CD8+ T cells after exosome stimulation. The effects of exosomes on the ability of CD8+ T cells to kill FaDu cells were assessed by CCK-8 assay. The expression of IL-10 and TGF-β1 was measured by enzyme-linked immunosorbent assay (ELISA). PD-L1 expression in HPC tissue samples was evaluated by immunohistochemistry, and the relationship between PD-1/PD-L1 expression and prognosis was investigated with patient specimens. Results PD-1 expression was significantly upregulated on CD8+ T cells in tumor tissues compared with those in normal tissues. The overall survival (OS) and disease-free survival (DFS) of PD-1-overexpressing patients were decreased. Serum exosomes from patients can elevate PD-1 expression on CD8+ T cells and suppress their killing capacity and secretory function. The rate of positive PD-L1 expression was increased in HPC tissues compared with paracancerous tissues. The DFS and OS of the PD-1(+)-PD-L1(+) group were significantly lower than those of the PD-1(−)-PD-L1(−) group. Conclusion Our findings indicate that serum exosomes from HPC patients can inhibit CD8+ T cell function and that the PD-1-PD-L1 pathway plays an important role in the immune escape of HPC. Exosomes combined with immunotherapy may guide the treatment of patients with advanced disease in the future.

Sign in / Sign up

Export Citation Format

Share Document