scholarly journals TCR affinity controls the dynamics but not the functional specification of the Th1 response to mycobacteria

2020 ◽  
Author(s):  
Nayan D Bhattacharyya ◽  
Claudio Counoupas ◽  
Lina Daniel ◽  
Guoliang Zhang ◽  
Stuart J Cook ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Division ◽  
T Cell ◽  
Immune Surveillance ◽  
Mycobacterial Infection ◽  
T Cell Response ◽  
Functional Specification ◽  
Tcr Affinity ◽  
Persistent Pathogens

AbstractThe quality of T cell responses depends on the lymphocytes’ ability to undergo clonal expansion, acquire effector functions and traffic to the site of infection. Although TCR signal strength is thought to dominantly shape the T cell response, by using TCR transgenic CD4+ T cells with different pMHC binding affinity, we reveal that TCR affinity does not control Th1 effector function acquisition nor the functional output of individual effectors following mycobacterial infection. Rather, TCR affinity calibrates the rate of cell division to synchronize the distinct processes of T cell proliferation, differentiation and trafficking. By timing cell division-dependent IL-12R expression, TCR affinity controls when T cells become receptive to Th1-imprinting IL-12 signals, determining the emergence and magnitude of the Th1 effector pool. These findings reveal a distinct yet cooperative role for IL-12 and TCR signalling in Th1 differentiation and suggests that the temporal activation of clones with different TCR affinity is a major strategy to coordinate immune surveillance against persistent pathogens.

TCR Affinity Controls the Dynamics but Not the Functional Specification of the Antimycobacterial CD4+ T Cell Response

2021 ◽  
pp. ji2001271
Author(s):  
Nayan D. Bhattacharyya ◽  
Claudio Counoupas ◽  
Lina Daniel ◽  
Guoliang Zhang ◽  
Stuart J. Cook ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Functional Specification ◽  
Tcr Affinity

scholarly journals Impaired Quality of the Hepatitis B Virus (HBV)-Specific T-Cell Response in Human Immunodeficiency Virus Type 1-HBV Coinfection

2009 ◽  
Vol 83 (15) ◽  
pp. 7649-7658 ◽  
Author(s):  
J. Judy Chang ◽  
Sunee Sirivichayakul ◽  
Anchalee Avihingsanon ◽  
Alex J. V. Thompson ◽  
Peter Revill ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
T Cell Response ◽  
Cell Responses ◽  
B Virus ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Hepatits B virus (HBV)-specific T cells play a key role both in the control of HBV replication and in the pathogenesis of liver disease. Human immunodeficiency virus type 1 (HIV-1) coinfection and the presence or absence of HBV e (precore) antigen (HBeAg) significantly alter the natural history of chronic HBV infection. We examined the HBV-specific T-cell responses in treatment-naïve HBeAg-positive and HBeAg-negative HIV-1-HBV-coinfected (n = 24) and HBV-monoinfected (n = 39) Asian patients. Peripheral blood was stimulated with an overlapping peptide library for the whole HBV genome, and tumor necrosis factor alpha and gamma interferon cytokine expression in CD8+ T cells was measured by intracellular cytokine staining and flow cytometry. There was no difference in the overall magnitude of the HBV-specific T-cell responses, but the quality of the response was significantly impaired in HIV-1-HBV-coinfected patients compared with monoinfected patients. In coinfected patients, HBV-specific T cells rarely produced more than one cytokine and responded to fewer HBV proteins than in monoinfected patients. Overall, the frequency and quality of the HBV-specific T-cell responses increased with a higher CD4+ T-cell count (P = 0.018 and 0.032, respectively). There was no relationship between circulating HBV-specific T cells and liver damage as measured by activity and fibrosis scores, and the HBV-specific T-cell responses were not significantly different in patients with either HBeAg-positive or HBeAg-negative disease. The quality of the HBV-specific T-cell response is impaired in the setting of HIV-1-HBV coinfection and is related to the CD4+ T-cell count.

scholarly journals mRNA vaccine-induced SARS-CoV-2-specific T cells recognize B.1.1.7 and B.1.351 variants but differ in longevity and homing properties depending on prior infection status

2021 ◽  
Author(s):  
Jason Neidleman ◽  
Xiaoyu Luo ◽  
Matthew McGregor ◽  
Guorui Xie ◽  
Victoria Murray ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Vaccine Dose ◽  
T Cell Response ◽  
Immune Defense ◽  
Cell Numbers ◽  
Prior Infection

While mRNA vaccines are proving highly efficacious against SARS-CoV-2, it is important to determine how booster doses and prior infection influence the immune defense they elicit, and whether they protect against variants. Focusing on the T cell response, we conducted a longitudinal study of infection-naive and COVID-19 convalescent donors before vaccination and after their first and second vaccine doses, using a high-parameter CyTOF analysis to phenotype their SARS-CoV-2-specific T cells. Vaccine-elicited spike-specific T cells responded similarly to stimulation by spike epitopes from the ancestral, B.1.1.7 and B.1.351 variant strains, both in terms of cell numbers and phenotypes. In infection-naive individuals, the second dose boosted the quantity but not quality of the T cell response, while in convalescents the second dose helped neither. Spike-specific T cells from convalescent vaccinees differed strikingly from those of infection-naive vaccinees, with phenotypic features suggesting superior long-term persistence and ability to home to the respiratory tract including the nasopharynx. These results provide reassurance that vaccine-elicited T cells respond robustly to the B.1.1.7 and B.1.351 variants, confirm that convalescents may not need a second vaccine dose, and suggest that vaccinated convalescents may have more persistent nasopharynx-homing SARS-CoV-2-specific T cells compared to their infection-naive counterparts.

scholarly journals Prior Dengue Virus Exposure Shapes T Cell Immunity to Zika Virus in Humans

2017 ◽  
Vol 91 (24) ◽  
Author(s):  
Alba Grifoni ◽  
John Pham ◽  
John Sidney ◽  
Patrick H. O'Rourke ◽  
Sinu Paul ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Zika Virus ◽  
T Cell Responses ◽  
Cross Reactivity ◽  
T Cell Response ◽  
T Cell Immunity ◽  
Cell Responses ◽  
Cell Immunity

ABSTRACT While progress has been made in characterizing humoral immunity to Zika virus (ZIKV) in humans, little is known regarding the corresponding T cell responses to ZIKV. Here, we investigate the kinetics and viral epitopes targeted by T cells responding to ZIKV and address the critical question of whether preexisting dengue virus (DENV) T cell immunity modulates these responses. We find that memory T cell responses elicited by prior infection with DENV or vaccination with tetravalent dengue attenuated vaccines (TDLAV) recognize ZIKV-derived peptides. This cross-reactivity is explained by the sequence similarity of the two viruses, as the ZIKV peptides recognized by DENV-elicited memory T cells are identical or highly conserved in DENV and ZIKV. DENV exposure prior to ZIKV infection also influences the timing and magnitude of the T cell response. ZIKV-reactive T cells in the acute phase of infection are detected earlier and in greater magnitude in DENV-immune patients. Conversely, the frequency of ZIKV-reactive T cells continues to rise in the convalescent phase in DENV-naive donors but declines in DENV-preexposed donors, compatible with more efficient control of ZIKV replication and/or clearance of ZIKV antigen. The quality of responses is also influenced by previous DENV exposure, and ZIKV-specific CD8 T cells from DENV-preexposed donors selectively upregulated granzyme B and PD1, unlike DENV-naive donors. Finally, we discovered that ZIKV structural proteins (E, prM, and C) are major targets of both the CD4 and CD8 T cell responses, whereas DENV T cell epitopes are found primarily in nonstructural proteins. IMPORTANCE The issue of potential ZIKV and DENV cross-reactivity and how preexisting DENV T cell immunity modulates Zika T cell responses is of great relevance, as the two viruses often cocirculate and Zika virus has been spreading in geographical regions where DENV is endemic or hyperendemic. Our data show that memory T cell responses elicited by prior infection with DENV recognize ZIKV-derived peptides and that DENV exposure prior to ZIKV infection influences the timing, magnitude, and quality of the T cell response. Additionally, we show that ZIKV-specific responses target different proteins than DENV-specific responses, pointing toward important implications for vaccine design against this global threat.

scholarly journals CD8+ T Cells Implicated in the Pathogenesis of Allergic Fungal Rhinosinusitis

2014 ◽  
Vol 5 (3) ◽  
pp. ar.2014.5.0103 ◽  
Author(s):  
Harshita Pant ◽  
Peta Macardle
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Cell Division ◽  
T Cell ◽  
T Cell Response ◽  
T Cell Subsets ◽  
T Cell Proliferation ◽  
Fungal Rhinosinusitis ◽  
Allergic Fungal Rhinosinusitis ◽  
Fungal Allergy

Fungi in paranasal sinuses are characteristic and considered a major pathogenic factor in a subset of chronic rhinosinusitis (CRS) patients, known as allergic fungal rhinosinusitis (AFRS). CD8+ T cells are enriched in AFRS sinuses but their role in fungal-specific responses is unknown. Alternaria alternata– and Aspergillus fumigatus–specific T lymphocyte responses were investigated in 6 AFRS patients, 10 eosinophilic mucus CRS (EMCRS) patients, 10 CRS with nasal polyps (CRSwNPs) patients, 6 allergic rhinitis with fungal allergy (ARFA) patients, and five controls. Fungal-specific proliferation of human peripheral blood mononuclear cells (PBMCs) was studied prospectively. Proliferating cells were examined for CD3, CD4, CD8, and CD25 expression. Relevant clinical characteristics, fungal allergy, detection of fungi in sinuses, and CD4+ and CD8+ composition of sinus T cells were also examined. CD4+ T-cell division to fungi occurred in all samples, regardless of fungal allergy or CRS. Fungal-specific CD8+ T-cell division occurred in all ARFA and control samples and the majority of CRSwNP patients; however, CD8+ T cells failed to proliferate in AFRS and EMCRS patients. The CD8+ T cells from AFRS patients also did not up-regulate the activation marker, CD25, with fungal antigen exposure. Presence of A. alternata– and A. fumigatus–specific CD4+ and CD8+ T-cell proliferation in healthy individuals, ARFA, and CRSwNP patients suggests that both T-cell subsets may be important in immune responses to these fungi. In AFRS and EMCRS patients, only fungal-specific CD4+ T-cell proliferation occurred; hence, a lack of CD8+ T-cell proliferation and activation in the presence of sinus eosinophilic mucus in these patients, regardless of fungal allergy, is a novel finding. This raises the question whether a dysfunctional CD8+ T-cell response predisposes to ineffective clearance and accumulation of fungi in the sinuses of susceptible patients.

scholarly journals High Frequency of CD4+ T Cells Specific for the TB10.4 Protein Correlates with Protection against Mycobacterium tuberculosis Infection

2006 ◽  
Vol 74 (6) ◽  
pp. 3396-3407 ◽  
Author(s):  
Sandra Hervas-Stubbs ◽  
Laleh Majlessi ◽  
Marcela Simsova ◽  
Jana Morova ◽  
Marie-Jesus Rojas ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Cytotoxic T Lymphocyte ◽  
Cell Epitope ◽  
Mycobacterial Infection ◽  
T Cell Response ◽  
T Cell Epitopes ◽  
Mycobacterium Tuberculosis Infection ◽  
A Subunit

ABSTRACTTB10.4 is a newly identified antigen ofMycobacterium tuberculosisrecognized by human and murine T cells upon mycobacterial infection. Here, we show that immunization withMycobacterium bovisBCG induces a strong, genetically controlled, Th1 immune response against TB10.4 in mice. BALB/c and C57BL/6 strains behave as high and low responders to TB10.4 protein, respectively. The TB10.4:74-88 peptide was identified as an immunodominant CD4+T-cell epitope forH-2dmice. Since recent results, as well as the present study, have raised interest in TB10.4 as a subunit vaccine, we analyzed immune responses induced by this antigen delivered by a new vector, the adenylate cyclase (CyaA) ofBordetella pertussis. CyaA is able to target dendritic cells and to deliver CD4+or CD8+T-cell epitopes to the major histocompatibility complex class II/I molecule presentation pathways, triggering specific Th1 or cytotoxic T-lymphocyte (CTL) responses. Several CyaA harboring either the entire TB10.4 protein or various subfragments containing the TB10.4:20-28 CTL epitope were shown to induce TB10.4-specific Th1 CD4+and CD8+T-cell responses. However, none of the recombinant CyaA, injected in the absence of adjuvant, was able to induce protection againstM. tuberculosisinfection. In contrast, TB10.4 protein administered with a cocktail of strong adjuvants that triggered a strong Th1 CD4+T-cell response induced significant protection againstM. tuberculosischallenge. These results confirm the potential value of the TB10.4 protein as a candidate vaccine and show that the presence of high frequencies of CD4+T cells specific to this strong immunogen correlates with protection againstM. tuberculosisinfection.

scholarly journals Gammaherpesvirus Persistence Alters Key CD8 T-Cell Memory Characteristics and Enhances Antiviral Protection

2006 ◽  
Vol 80 (17) ◽  
pp. 8303-8315 ◽  
Author(s):  
Joshua J. Obar ◽  
Shinichiro Fuse ◽  
Erica K. Leung ◽  
Sarah C. Bellfy ◽  
Edward J. Usherwood
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Immune Surveillance ◽  
Interleukin 2 ◽  
T Cell Response ◽  
Unexpected Finding ◽  
Virus Persistence ◽  
Murine Gammaherpesvirus

ABSTRACT In herpesvirus infections, the virus persists for life but is contained through T-cell-mediated immune surveillance. How this immune surveillance operates is poorly understood. Recent studies of other persistent infections have indicated that virus persistence is associated with functional deficits in the CD8+ T-cell response. To test whether this is the case in a herpesvirus infection, we used a mutant murine gammaherpesvirus that is defective in its ability to persist in the host. By comparing the immune response to this virus with a revertant virus that can persist, we were able to dissect the changes in the antiviral CD8+ T-cell response that are induced by virus persistence. Surprisingly, persistently infected mice controlled a secondary challenge infection more rapidly than nonpersistently infected mice, indicating enhanced rather than diminished effector functions. Consistent with this, virus-specific CD8 T cells from these mice exhibited faster upregulation of the cytotoxic mediator granzyme B. Another unexpected finding was that CD8+ T cells from neither infection responded efficiently to homeostatic cytokines. The unresponsiveness of the memory cells from the nonpersistently infected mice appears to be linked to the prolonged replication of virus within the lungs. Other changes seen in different chronic infection models were also observed, such as changes in Bcl-2 levels, interleukin-2 production, and the immunodominance hierarchy. These data show persistence of gammaherpesvirus type 68 alters the properties of CD8+ T cells and illustrates that immune surveillance does not require CD8 T cells with the same attributes as “classical” memory CD8+ T cells.

scholarly journals Mechanisms that allow vaccination against an oncolytic vesicular stomatitis virus-encoded transgene to enhance safety without abrogating oncolysis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Amanda W. K. AuYeung ◽  
Robert C. Mould ◽  
Ashley A. Stegelmeier ◽  
Jacob P. van Vloten ◽  
Khalil Karimi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vesicular Stomatitis Virus ◽  
Cell Response ◽  
Viral Infections ◽  
T Cell Response ◽  
Oncolytic Viruses ◽  
Oncolytic Virotherapy ◽  
Cell Immunity ◽  
Vesicular Stomatitis

AbstractVaccination can prevent viral infections via virus-specific T cells, among other mechanisms. A goal of oncolytic virotherapy is replication of oncolytic viruses (OVs) in tumors, so pre-existing T cell immunity against an OV-encoded transgene would seem counterproductive. We developed a treatment for melanomas by pre-vaccinating against an oncolytic vesicular stomatitis virus (VSV)-encoded tumor antigen. Surprisingly, when the VSV-vectored booster vaccine was administered at the peak of the primary effector T cell response, oncolysis was not abrogated. We sought to determine how oncolysis was retained during a robust T cell response against the VSV-encoded transgene product. A murine melanoma model was used to identify two mechanisms that enable this phenomenon. First, tumor-infiltrating T cells had reduced cytopathic potential due to immunosuppression. Second, virus-induced lymphopenia acutely removed virus-specific T cells from tumors. These mechanisms provide a window of opportunity for replication of oncolytic VSV and rationale for a paradigm change in oncolytic virotherapy, whereby immune responses could be intentionally induced against a VSV-encoded melanoma-associated antigen to improve safety without abrogating oncolysis.

scholarly journals Host-derived lipids orchestrate pulmonary γδ T cell response to provide early protection against influenza virus infection

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xiaohui Wang ◽  
Xiang Lin ◽  
Zihan Zheng ◽  
Bingtai Lu ◽  
Jun Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Influenza Virus Infection ◽  
Γδ T Cells ◽  
T Cell Response ◽  
Host Cells ◽  
Interleukin 17 ◽  
Γδ T Cell ◽  
Innate Defense

AbstractInnate immunity is important for host defense by eliciting rapid anti-viral responses and bridging adaptive immunity. Here, we show that endogenous lipids released from virus-infected host cells activate lung γδ T cells to produce interleukin 17 A (IL-17A) for early protection against H1N1 influenza infection. During infection, the lung γδ T cell pool is constantly supplemented by thymic output, with recent emigrants infiltrating into the lung parenchyma and airway to acquire tissue-resident feature. Single-cell studies identify IL-17A-producing γδ T (Tγδ17) cells with a phenotype of TCRγδhiCD3hiAQP3hiCXCR6hi in both infected mice and patients with pneumonia. Mechanistically, host cell-released lipids during viral infection are presented by lung infiltrating CD1d+ B-1a cells to activate IL-17A production in γδ T cells via γδTCR-mediated IRF4-dependent transcription. Reduced IL-17A production in γδ T cells is detected in mice either lacking B-1a cells or with ablated CD1d in B cells. Our findings identify a local host-immune crosstalk and define important cellular and molecular mediators for early innate defense against lung viral infection.

scholarly journals Checkpoint blockade accelerates a novel switch from an NKT-driven TNFα response toward a T cell driven IFN-γ response within the tumor microenvironment

2021 ◽  
Vol 9 (6) ◽  
pp. e002269
Author(s):  
Shota Aoyama ◽  
Ryosuke Nakagawa ◽  
Satoshi Nemoto ◽  
Patricio Perez-Villarroel ◽  
James J Mulé ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Ex Vivo ◽  
T Cell Response ◽  
Effector Function ◽  
Checkpoint Blockade ◽  
Necrosis Factor Alpha ◽  
Ifn Γ

BackgroundThe temporal response to checkpoint blockade (CB) is incompletely understood. Here, we profiled the tumor infiltrating lymphocyte (TIL) landscape in response to combination checkpoint blockade at two distinct timepoints of solid tumor growth.MethodsC57BL/6 mice bearing subcutaneous MC38 tumors were treated with anti-PD-1 and/or anti-CTLA-4 antibodies. At 11 or 21 days, TIL phenotype and effector function were analyzed in excised tumor digests using high parameter flow cytometry. The contributions of major TIL populations toward overall response were then assessed using ex vivo cytotoxicity and in vivo tumor growth assays.ResultsThe distribution and effector function among 37 distinct TIL populations shifted dramatically between early and late MC38 growth. At 11 days, the immune response was dominated by Tumor necrosis factor alpha (TNFα)-producing NKT, representing over half of all TIL. These were accompanied by modest frequencies of natural killer (NK), CD4+, or CD8+ T cells, producing low levels of IFN-γ. At 21 days, NKT populations were reduced to a combined 20% of TIL, giving way to increased NK, CD4+, and CD8+ T cells, with increased IFN-γ production. Treatment with CB accelerated this switch. At day 11, CB reduced NKT to less than 20% of all TIL, downregulated TNFα across NKT and CD4+ T cell populations, increased CD4+ and CD8+ TIL frequencies, and significantly upregulated IFN-γ production. Degranulation was largely associated with NK and NKT TIL. Blockade of H-2kb and/or CD1d during ex vivo cytotoxicity assays revealed NKT has limited direct cytotoxicity against parent MC38. However, forced CD1d overexpression in MC38 cells significantly diminished tumor growth, suggesting NKT TIL exerts indirect control over MC38 growth.ConclusionsDespite an indirect benefit of early NKT activity, CB accelerates a switch from TNFα, NKT-driven immune response toward an IFN-γ driven CD4+/CD8+ T cell response in MC38 tumors. These results uncover a novel NKT/T cell switch that may be a key feature of CB response in CD1d+ tumors.

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