scholarly journals Proapoptotic Bcl-2 Family Member Bim Promotes Persistent Infection and Limits Protective Immunity

2007 ◽  
Vol 76 (3) ◽  
pp. 1179-1185 ◽  
Author(s):  
Stacie Reckling ◽  
Senad Divanovic ◽  
Christopher L. Karp ◽  
Sara Wojciechowski ◽  
Yasmine Belkaid ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Family Member ◽  
Persistent Infection ◽  
Protective Immunity ◽  
Leishmania Major ◽  
Interleukin 10 ◽  
Effector T Cells ◽  
T Cell Response ◽  
Ifn Γ

ABSTRACT Following the peak of the T-cell response, most of the activated effector T cells die by apoptosis driven by the proapoptotic Bcl-2 family member Bim (Bcl-2-interacting mediator of death). Whether the absence of Bim-mediated T-cell apoptosis can affect protective immunity remains unclear. Here, we used a mouse model of Leishmania major infection, in which parasite persistence and protective immunity are controlled by an equilibrium reached between parasite-specific gamma interferon (IFN-γ)-producing effector T cells and interleukin-10 (IL-10)-producing CD4+ CD25+ T regulatory cells. To further understand the role of Bim-mediated apoptosis in persistent infection and protective immunity, we infected Bim −/− mice with L. major. We found that the initial parasite growth and lesion development were similar in Bim −/− and wild-type mice after primary L. major infection. However, at later times after infection, Bim −/− mice had significantly increased L. major-specific CD4+ T-cell responses and were resistant to persistent infection. Interestingly, despite their resistance to primary L. major infection, Bim −/− mice displayed significantly enhanced protection against challenge with L. major. Increased resistance to challenge in Bim −/− mice was associated with a significant increase in the number of L. major-specific IFN-γ-producing CD4+ T cells and a lack of IL-10 production at the challenge site. Taken together, these data suggest that Bim limits protective immunity and that the absence of Bim allows the host to bypass antigen persistence for maintenance of immunity against reinfection.

scholarly journals Early Induction of Interleukin-10 Limits Antigen-Specific CD4+T Cell Expansion, Function, and Secondary Recall Responses during Persistent Phagosomal Infection

2014 ◽  
Vol 82 (10) ◽  
pp. 4092-4103 ◽  
Author(s):  
Abinav Kumar Singh ◽  
Nagaraja R. Thirumalapura
Keyword(s):  
T Cells ◽  
T Cell ◽  
Functional Status ◽  
Persistent Infection ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Interleukin 10 ◽  
Host Cells ◽  
Content Type ◽  
Ifn Γ

ABSTRACTDiverse pathogens have evolved to survive and replicate in the endosomes or phagosomes of the host cells and establish persistent infection. Ehrlichiae are Gram-negative, intracellular bacteria that are transmitted by ticks. Ehrlichiae reside in the endosomes of the host phagocytic or endothelial cells and establish persistent infection in their vertebrate reservoir hosts. CD4+T cells play a critical role in protection against phagosomal infections. In the present study, we investigated the expansion, maintenance, and functional status of antigen-specific CD4+T cells during persistentEhrlichia murisinfection in wild-type and interleukin-10 (IL-10)-deficient mice. Our study indicated that early induction of IL-10 led to reduced inflammatory responses and impaired bacterial clearance during persistentEhrlichiainfection. Notably, we demonstrated that the functional production of gamma interferon (IFN-γ) by antigen-specific CD4+T cells maintained during a persistent phagosomal infection progressively deteriorates. The functional loss of IFN-γ production by antigen-specific CD4+T cells was reversed in the absence of IL-10. Furthermore, we demonstrated that transient blockade of IL-10 receptor during the T cell priming phase early in infection was sufficient to enhance the magnitude and the functional capacity of antigen-specific effector and memory CD4+T cells, which translated into an enhanced recall response. Our findings provide new insights into the functional status of antigen-specific CD4+T cells maintained during persistent phagosomal infection. The study supports the concept that a better understanding of the factors that influence the priming and differentiation of CD4+T cells may provide a basis to induce a protective immune response against persistent infections.

scholarly journals MycobacteriumulceransTriggers T-Cell Immunity followed by Local and Regional but Not Systemic Immunosuppression

2010 ◽  
Vol 79 (1) ◽  
pp. 421-430 ◽  
Author(s):  
Alexandra G. Fraga ◽  
Andrea Cruz ◽  
Teresa G. Martins ◽  
Egídio Torrado ◽  
Margarida Saraiva ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protective Immunity ◽  
T Cell Response ◽  
Mycobacterium Ulcerans ◽  
Therapeutic Interventions ◽  
Cutaneous Lesions ◽  
Systemic Immunosuppression ◽  
Cell Immunity ◽  
Ifn Γ

ABSTRACTBuruli ulcer is a neglected infectious disease caused byMycobacterium ulceransand is characterized by necrotic cutaneous lesions induced by the exotoxin mycolactone. Despite evidence of Th1-mediated protective immunity,M. ulceransinfection has been associated with systemic immunosuppression. We show that early during mouse infection with either mycolactone-positive or negative strains, pathogen-specific gamma interferon (IFN-γ)-producing T cells developed in the draining lymph node (DLN). CD4+cells migrated to the infection foci, but progressive infection with virulentM. ulceransled to the local depletion of recruited cells. Moreover, dissemination of virulentM. ulceransto the DLN was accompanied by extensive DLN apoptotic cytopathology, leading to depletion of CD4+T cells and abrogation of IFN-γ expression. Advanced footpad infection with virulentM. ulceransdid not induce increased susceptibility to systemic coinfection byListeria monocytogenes. These results show that infection withM. ulceransefficiently triggers a mycobacterium-specific T-cell response in the DLN and that progression of infection with highly virulentM. ulceransleads to a local and regional suppression of that immune response, but without induction of systemic immunosuppression. These results suggest that prophylactic and/or therapeutic interventions to prevent dissemination ofM. ulceransto DLN during the early phase of infection would contribute for the maintenance of protective immunity and disease control.

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.

scholarly journals Vaccination with DNA Encoding the Immunodominant LACK Parasite Antigen Confers Protective Immunity to Mice Infected with Leishmania major

1997 ◽  
Vol 186 (7) ◽  
pp. 1137-1147 ◽  
Author(s):  
Sanjay Gurunathan ◽  
David L. Sacks ◽  
Daniel R. Brown ◽  
Steven L. Reiner ◽  
Hughes Charest ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Protective Immunity ◽  
Leishmania Major ◽  
Protective Efficacy ◽  
Dna Vaccination ◽  
Attractive Alternative ◽  
Dna Immunization ◽  
Dna Encoding ◽  
Ifn Γ

To determine whether DNA immunization could elicit protective immunity to Leishmania major in susceptible BALB/c mice, cDNA for the cloned Leishmania antigen LACK was inserted into a euykaryotic expression vector downstream to the cytomegalovirus promoter. Susceptible BALB/c mice were then vaccinated subcutaneously with LACK DNA and challenged with L. major promastigotes. We compared the protective efficacy of LACK DNA vaccination with that of recombinant LACK protein in the presence or absence of recombinant interleukin (rIL)-12 protein. Protection induced by LACK DNA was similar to that achieved by LACK protein and rIL-12, but superior to LACK protein without rIL-12. The immunity conferred by LACK DNA was durable insofar as mice challenged 5 wk after vaccination were still protected, and the infection was controlled for at least 20 wk after challenge. In addition, the ability of mice to control infection at sites distant to the site of vaccination suggests that systemic protection was achieved by LACK DNA vaccination. The control of disease progression and parasitic burden in mice vaccinated with LACK DNA was associated with enhancement of antigen-specific interferon-γ (IFN-γ) production. Moreover, both the enhancement of IFN-γ production and the protective immune response induced by LACK DNA vaccination was IL-12 dependent. Unexpectedly, depletion of CD8+ T cells at the time of vaccination or infection also abolished the protective response induced by LACK DNA vaccination, suggesting a role for CD8+ T cells in DNA vaccine induced protection to L. major. Thus, DNA immunization may offer an attractive alternative vaccination strategy against intracellular pathogens, as compared with conventional vaccination with antigens combined with adjuvants.

scholarly journals Combination of a Sindbis-SARS-CoV-2 spike vaccine and αOX40 antibody elicits protective immunity against SARS-CoV-2 induced disease and potentiates long-term SARS-CoV-2-specific humoral and T-cell immunity

2021 ◽  
Author(s):  
Antonella Scaglione ◽  
Silvana Opp ◽  
Alicia Hurtado ◽  
Christine Pampeno ◽  
Ziyan Lin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protective Immunity ◽  
T Cell Response ◽  
Spike Protein ◽  
Effector Memory ◽  
World Population ◽  
Vaccine Platform ◽  
Vaccine Approach

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 is a major global public threat. Currently, a worldwide effort has been mounted to generate billions of effective SARS-CoV-2 vaccine doses to immunize the world population at record speeds. However, there is still demand for alternative effective vaccines that rapidly confer long-term protection and rely upon cost-effective, easily scaled-up manufacturing. Here, we present a Sindbis alphavirus vector (SV), transiently expressing the SARS-CoV-2 spike protein (SV.Spike), combined with the OX40 immunostimulatory antibody (OX40) as a novel, highly effective vaccine approach. We show that SV.Spike plus αOX40 elicits long-lasting neutralizing antibodies and a vigorous T cell response in mice. Protein binding, immunohistochemical and cellular infection assays all show that vaccinated mice sera inhibits spike functions. Immunophenotyping, RNA Seq transcriptome profiles and metabolic analysis indicate a reprogramming of T cells in vaccinated mice. Activated T cells were found to mobilize to lung tissue. Most importantly, SV.Spike plus αOX40 provided robust immune protection against infection with authentic coronavirus in transgenic mice expressing the human ACE2 receptor (hACE2-Tg). Finally, our immunization strategy induced strong effector memory response, potentiating protective immunity against re-exposure to SARS-CoV-2 spike protein. Our results show the potential of a new Sindbis virus-based vaccine platform to counteract waning immune response that can be used as a new candidate to combat SARS-CoV-2. Given the strong T cell responses elicited, our vaccine is likely to be effective against variants that are proving challenging, as well as, serve as a platform to develop a broader spectrum pancoronavirus vaccine. Similarly, the vaccine approach is likely to be applicable to other pathogens.

scholarly journals Sunitinib Exerts In Vitro Immunomodulatory Activity on Sarcomas via Dendritic Cells and Synergizes With PD-1 Blockade

2021 ◽  
Vol 12 ◽  
Author(s):  
Darina Ocadlikova ◽  
Mariangela Lecciso ◽  
Javier Martin Broto ◽  
Katia Scotlandi ◽  
Michele Cavo ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cell Lines ◽  
Effector T Cells ◽  
Sarcoma Cell ◽  
Ifn Γ ◽  
Sarcoma Cells

BackgroundHigh-grade sarcomas are a heterogeneous group of aggressive tumors arising in bone and soft tissues. After relapse, treatment options are limited. The multi-targeted receptor tyrosine kinase inhibitors (TKIs) sunitinib and inhibitor of PD-1 (anti-PD-1) nivolumab have shown antitumor activity in selected subtypes. In this study, we examine the role of TKIs and PD-1 based therapy in in vitro cocultures of sarcoma.MethodsThe human osteosarcoma (SaOS-2) and synovial sarcoma (SYO-1) cell lines were treated with sunitinib. After cell death and proliferation assessment, expression of PD-L1 was analyzed by flow cytometry. Sunitinib-treated sarcoma cells were cocultured with dendritic cells (DCs), and the phenotype of mature DCs was determined by flow cytometry. Mature DCs were cultured with autologous T cells. PD-1 expression on T cells, their proliferation, T regulatory cell (Tregs) induction and IFN-γ production, before and after nivolumab exposure, were analyzed.ResultsAlong with its anti-proliferative and direct pro-apoptotic effect on sarcoma cell lines, sunitinib prompted PD-L1 upregulation on sarcoma cells. Interestingly, sunitinib-treated sarcoma cells drive DCs to full maturation and increase their capacity to induce sarcoma-reactive T cells to produce IFN-γ. Conversely, no effect on T cell proliferation and T cell subpopulation composition was observed. Moreover, both bone and synovial sarcoma cell lines induced Tregs through DCs but sunitinib treatment completely abrogated Treg induction. Finally, sarcoma cell lines induced PD-1 upregulation on both effector T cells and Tregs when loaded into DCs, providing a rationale for using PD-1 blockade. Indeed, PD-1 blockade by nivolumab synergized with sunitinib in inducing IFN-γ-producing effector T cells.ConclusionsTaken together, our in vitro data indicate that the treatment of sarcoma cells with sunitinib can exert significant changes on immune cell subsets toward immune activation, leading to DC-based cross-priming of IFN-γ-producing effector T cells and reduced Treg induction. PD-1 blockade with nivolumab has a synergistic effect with sunitinib, supporting the use of TKI and anti-PD-1 approach in sarcomas, and perhaps in other cancers. DC-targeted drugs, including toll-like receptor 3 inhibitors and CD47 inhibitors, are under development and our preclinical model might help to better design their clinical application.

scholarly journals Short-Lived Effector CD8 T Cells Induced by Genetically Attenuated Malaria Parasite Vaccination Express CD11c

2013 ◽  
Vol 81 (11) ◽  
pp. 4171-4181 ◽  
Author(s):  
Laura A. Cooney ◽  
Megha Gupta ◽  
Sunil Thomas ◽  
Sebastian Mikolajczak ◽  
Kimberly Y. Choi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Inflammatory Cytokines ◽  
Plasmodium Yoelii ◽  
T Cell Response ◽  
Parasite Development ◽  
Effector Memory ◽  
Cell Phenotype ◽  
Effector Cells ◽  
Ifn Γ

ABSTRACTVaccination with a single dose of genetically attenuated malaria parasites can induce sterile protection against sporozoite challenge in the rodentPlasmodium yoeliimodel. Protection is dependent on CD8+T cells, involves perforin and gamma interferon (IFN-γ), and is correlated with the expansion of effector memory CD8+T cells in the liver. Here, we have further characterized vaccine-induced changes in the CD8+T cell phenotype and demonstrated significant upregulation of CD11c on CD3+CD8b+T cells in the liver, spleen, and peripheral blood. CD11c+CD8+T cells are predominantly CD11ahiCD44hiCD62L−, indicative of antigen-experienced effector cells. Followingin vitrorestimulation with malaria-infected hepatocytes, CD11c+CD8+T cells expressed inflammatory cytokines and cytotoxicity markers, including IFN-γ, tumor necrosis factor alpha (TNF-α), interleukin-2 (IL-2), perforin, and CD107a. CD11c−CD8+T cells, on the other hand, expressed negligible amounts of all inflammatory cytokines and cytotoxicity markers tested, indicating that CD11c marks multifunctional effector CD8+T cells. Coculture of CD11c+, but not CD11c−, CD8+T cells with sporozoite-infected primary hepatocytes significantly inhibited liver-stage parasite development. Tetramer staining for the immunodominant circumsporozoite protein (CSP)-specific CD8+T cell epitope demonstrated that approximately two-thirds of CSP-specific cells expressed CD11c at the peak of the CD11c+CD8+T cell response, but CD11c expression was lost as the CD8+T cells entered the memory phase. Further analyses showed that CD11c+CD8+T cells are primarily KLRG1+CD127−terminal effectors, whereas all KLRG1−CD127+memory precursor effector cells are CD11c−CD8+T cells. Together, these results suggest that CD11c marks a subset of highly inflammatory, short-lived, antigen-specific effector cells, which may play an important role in eliminating infected hepatocytes.

scholarly journals The Role of Interleukin-10 (IL-10) in IL-15–Mediated T-Cell Responses

Blood ◽  
1997 ◽  
Vol 90 (11) ◽  
pp. 4513-4521 ◽  
Author(s):  
Dieter Körholz ◽  
Ursula Banning ◽  
Halvard Bönig ◽  
Markus Grewe ◽  
Marion Schneider ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Interleukin 10 ◽  
T Cell Proliferation ◽  
Cell Production ◽  
Cd25 Expression ◽  
Tnf Α ◽  
Ifn Γ

Abstract Interleukin-15 (IL-15) is a potent T-cell stimulating factor, which has recently been used for pre-clinical in vivo immunotherapy. Here, the IL-15 effect on CD3-stimulated peripheral human T cells was investigated. IL-15 induced a significant T-cell proliferation and upregulated CD25 expression. IL-15 significantly enhanced T-cell production of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and IL-10. Between 10- and 100-fold greater concentrations of IL-15 were necessary to reach a biological effect equivalent to that of IL-2. Blockade of IL-2 binding to the high-affinity IL-2 receptor did not affect the IL-15 effects, suggesting that IL-15 did not act by inducing endogenous IL-2. Exogenously administered IL-10 significantly reduced the IL-15 and IL-2–mediated IFN-γ and TNF-α production, whereas T-cell proliferation and CD25 expression were not affected. The inhibitory effects of exogenously administered IL-10 on T-cell cytokine production appeared indirect, and are likely secondary to decreased IL-12 production by accessory cells. Inhibition of endogenous IL-10 binding to the IL-10 receptor significantly increased IFN-γ and TNF-α release from T cells. These data suggest that endogenous IL-10 can regulate activated T-cell production of IFN-γ and TNF-α via a paracrine negative feedback loop. The observations of this study could be of relevance for the therapeutic use of IL-15 in vivo.

scholarly journals Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells

2005 ◽  
Vol 202 (7) ◽  
pp. 885-891 ◽  
Author(s):  
Kuibeom Ko ◽  
Sayuri Yamazaki ◽  
Kyoko Nakamura ◽  
Tomohisa Nishioka ◽  
Keiji Hirota ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Effector T Cells ◽  
Tumor Rejection ◽  
Cell Stimulation ◽  
T Cell Stimulation ◽  
Ifn Γ ◽  
Advanced Tumors

T cell stimulation via glucocorticoid-induced tumor necrosis factor receptor family–related protein (GITR) can evoke effective tumor immunity. A single administration of agonistic anti-GITR monoclonal antibody (mAb) to tumor-bearing mice intravenously or directly into tumors provoked potent tumor-specific immunity and eradicated established tumors without eliciting overt autoimmune disease. A large number of CD4+ and CD8+ T cells, including interferon (IFN)-γ–secreting cells, infiltrated regressing tumors. Tumor-specific IFN-γ–secreting CD4+ and CD8+ T cells also increased in the spleen. The treatment led to tumor rejection in IFN-γ–intact mice but not IFN-γ–deficient mice. Furthermore, coadministration of anti-GITR and anti–CTLA-4 mAbs had a synergistic effect, leading to eradication of more advanced tumors. In contrast, coadministration of anti-CD25 and anti-GITR mAbs was less effective than anti-GITR treatment alone, because anti-CD25 depleted both CD25+-activated effector T cells and CD25+CD4+ naturally occurring regulatory T (T reg) cells. Importantly, CD4+ T cells expressing the T reg–specific transcription factor Foxp3 predominantly infiltrated growing tumors in control mice, indicating that tumor-infiltrating natural Foxp3+CD25+CD4+ T reg cells may hamper the development of effective tumor immunity. Taken together, T cell stimulation through GITR attenuates T reg–mediated suppression or enhances tumor-killing by CD4+ and CD8+ effector T cells, including those secreting IFN-γ, or both. Agonistic anti-GITR mAb is therefore instrumental in treating advanced cancers.

scholarly journals The Polyomavirus BK Large T-Antigen-Derived Peptide Elicits an HLA-DR Promiscuous and Polyfunctional CD4+T-Cell Response

2011 ◽  
Vol 18 (5) ◽  
pp. 815-824 ◽  
Author(s):  
Bala Ramaswami ◽  
Iulia Popescu ◽  
Camila Macedo ◽  
Chunqing Luo ◽  
Ron Shapiro ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
T Antigen ◽  
T Cell Response ◽  
Peptide Sequence ◽  
Large T Antigen ◽  
Hla Dr ◽  
Ifn Γ

ABSTRACTBK virus (BKV) nephropathy and hemorrhagic cystitis are increasingly recognized causes of disease in renal and hematopoietic stem cell transplant recipients, respectively. Functional characterization of the immune response to BKV is important for clinical diagnosis, prognosis, and vaccine design. A peptide mix (PepMix) and overlapping (OPP) or random (RPP) peptide pools derived from BKV large T antigen (LTA) were used to restimulate 14-day-expanded peripheral blood mononuclear cells (PBMC) from 27 healthy control subjects in gamma interferon (IFN-γ)-specific enzyme-linked immunospot (ELISPOT) assays. A T-cell response to LTA PepMix was detected in 15/27 subjects. A response was frequently observed with peptides derived from the helicase domain (9/15 subjects), while the DNA binding and host range domains were immunologically inert (0/15 subjects). For all nine subjects who responded to LTA peptide pools, the immune response could be explained largely by a 15-mer peptide designated P313. P313-specific CD4+T-cell clones demonstrated (i) stringent LTA peptide specificity; (ii) promiscuous recognition in the context of HLA-DR alleles; (iii) cross recognition of homologous peptides from the polyomavirus simian virus 40 (SV40); (iv) an effector memory phenotype, CD107a expression, and intracellular production of IFN-γ and tumor necrosis factor alpha (TNF-α); (v) cytotoxic activity in a chromium release assay; and (vi) the ability to directly present cognate antigen to autologous T cells. In conclusion, T-cell-mediated immunity to BKV in healthy subjects is associated with a polyfunctional population of CD4+T cells with dual T-helper and T-cytotoxic properties. HLA class II promiscuity in antigen presentation makes the targeted LTA peptide sequence a suitable candidate for inclusion in immunotherapy protocols.

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