CD4 T Cells Specific for a Latency-Associated γ-Herpesvirus Epitope Are Polyfunctional and Cytotoxic

Freeman, Michael L.; Burkum, Claire E.; Cookenham, Tres; Roberts, Alan D.; Lanzer, Kathleen G.; Huston, Gail E.; Jensen, Meghan K.; Sidney, John; Peters, Bjoern; Kohlmeier, Jacob E.; Woodland, David L.; Dyk, Linda F. van; Sette, Alessandro; Blackman, Marcia A.

doi:10.4049/jimmunol.1302060

Cited by 18 publications

(18 citation statements)

References 44 publications

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“…Conversely, a greater number of CD8 + T cells exhibited a lytic phenotype; those that secreted IFNγ were more likely to simultaneously express CD107a as well. These data support other reports that CD4 + T cells can exhibit cytolytic activity [49-52] and provide insight into the heterogenous behavior of T cells expressing the same TCR.…”

Section: Discussionsupporting

confidence: 91%

TCR gene-modified T cells can efficiently treat established hepatitis C-associated hepatocellular carcinoma tumors

Spear

Callender

Roszkowski

et al. 2016

Cancer Immunol Immunother

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The success in recent clinical trials using T cell receptor (TCR)-genetically engineered T cells to treat melanoma has encouraged the use of this approach toward other malignancies and viral infections. Although hepatitis C virus (HCV) infection is being treated with a new set of successful direct anti-viral agents, potential for virologic breakthrough or relapse by immune escape variants remains. Additionally, many HCV+ patients have HCV-associated disease, including hepatocellular carcinoma (HCC), does not respond to these novel drugs. Further exploration of other approaches to address HCV infection and its associated disease is highly warranted. Here, we demonstrate the therapeutic potential of PBL-derived T cells genetically engineered with a high affinity, HLA-A2-restricted, HCV NS3:1406-1415-reactive TCR. HCV1406 TCR-transduced T cells can recognize naturally processed antigen and elicit CD8-independent recognition of both peptide-loaded targets and HCV+ human HCC cell lines. Furthermore, these cells can mediate regression of established HCV+ HCC in vivo. Our results suggest that HCV TCR-engineered antigen-reactive T cells may be a plausible immunotherapy option to treat HCV-associated malignancies, such as HCC.

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Section: Discussionsupporting

confidence: 91%

TCR gene-modified T cells can efficiently treat established hepatitis C-associated hepatocellular carcinoma tumors

Spear

Callender

Roszkowski

et al. 2016

Cancer Immunol Immunother

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“…MHC-II restricted cytotoxicity offers an alternate mechanism for host recognition and clearance of virally-infected cells. Indeed several groups have reported key roles for MHC-II restricted cytotoxicity during infection with IAV (25), LCMV (26), Sendai virus (27), and γ-herpesvirus-68 (28). This supports the efficacy of ThCTL killing, especially given the fact that multiple arms of the immune system often work both independently and in synergy to promote clearance of IAV (17, 25, 29, 30) and other viruses (31).…”

Section: Introductionmentioning

confidence: 99%

NKG2C/E Marks the Unique Cytotoxic CD4 T Cell Subset, ThCTL, Generated by Influenza Infection

Marshall

Vong

Devarajan

et al. 2017

The Journal of Immunology

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CD4 T cells can differentiate into multiple effector subsets, including ThCTL that mediate MHC-II restricted cytotoxicity. Although CD4 T cell mediated cytotoxicity has been reported in multiple viral infections, their characteristics and the factors regulating their generation are unclear, in part due to a lack of a signature marker. We show here that in mice, NKG2C/E identifies the ThCTL that develop in the lung during influenza A virus (IAV) infection. ThCTL express the NKG2X/CD94 complex, in particular the NKG2C/E isoforms. NKG2C/E+ ThCTL are part of the lung CD4 effector population and they mediate IAV-specific cytotoxic activity. The phenotype of NKG2C/E+ ThCTL indicates they are highly activated effectors expressing high levels of binding to P-selectin, T-bet and Blimp-1, and that more of them secrete IFNγ and readily degranulate than non-ThCTL. ThCTL also express more cytotoxicity-associated genes including perforin and granzymes and fewer genes associated with recirculation and memory. They are found only at the site of infection and not in other peripheral sites. These data suggest ThCTL are marked by the expression of NKG2C/E and represent a unique CD4 effector population specialized for cytotoxicity.

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“…At 14d post-challenge, CD4+ T-cell transfer had minimal impact on the number of latently infected cells (Fig. 5A) despite evidence that CD4+ T cells are cytotoxic to herpesviruses 34–36 . The transfer of WT-primed CD8+ T-cells caused a five-fold reduction in reactivated latently infected cells.…”

Section: Resultsmentioning

confidence: 98%

Deletion of immune evasion genes provides an effective vaccine design for tumor-associated herpesviruses

Brar

Czudnochowski

Sukhina

et al. 2020

Preprint

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1Vaccines based on live attenuated viruses often induce broad, multifaceted immune 2 responses. However, they also usually sacrifice immunogenicity for attenuation. It is 3 particularly difficult to elicit an effective vaccine for herpesviruses due to an armament of 4 immune evasion genes and a latent phase. Here, to overcome the limitation of 5 attenuation, we developed a rational herpesvirus vaccine in which viral immune evasion 6 genes were deleted to enhance immunogenicity while also attaining safety. To test this 7 vaccine strategy, we utilized murine gammaherpesvirus-68 (MHV-68) as a proof-of-8 concept model for the cancer-associated human -herpesviruses, Epstein-Barr virus and 9Kaposi sarcoma-associated herpesvirus. We engineered a recombinant MHV-68 virus by 10 targeted inactivation of viral antagonists of type I interferon (IFN-I) pathway and deletion 11 of the latency locus responsible for persistent infection. This recombinant virus is highly 12 attenuated with no measurable capacity for replication, latency, or persistence in 13 immunocompetent hosts. It stimulates robust innate immunity, differentiates virus-specific 14 memory T cells, and elicits neutralizing antibodies. A single vaccination affords durable 15 protection that blocks the establishment of latency following challenge with the wild type 16 MHV-68 for at least six months post-vaccination. These results provide a novel approach 17 to effective vaccination against cancer-associated herpesviruses through the elimination 18 of latency and key immune evasion mechanisms from the pathogen. 19 20 Keywords: attenuation, -herpesviruses, immunogenicity, immune evasion, latency, T-21 cell, tumorigenesis, type I interferon, vaccine 22 herpesvirus (KSHV) are associated with cancer, and with no effective vaccine remain a 25 global health challenge. Despite strong innate and adaptive immune responses, once 26 acquired, herpesviruses persist for the rest of the host's life. EBV is associated with 27Burkitt's lymphoma, nasopharyngeal carcinoma (NPC), and Hodgkin'sand non-28Hodgkin's lymphomas 1-3 while KSHV is associated with Kaposi's sarcoma (KS), primary 29 effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). These 30 malignancies frequently develop in AIDS patients 4-6 , but also in immunocompetent 31 people with more than 160,000 annual cancer cases associated with EBV and KSHV 7 . 32Clearly, effective vaccines against human -herpesviruses would dramatically reduce the 33 incidence of malignancies associated with these viruses. 34 35 Herpesviruses establish persistent infections characterized by lytic replication and 36 latency. Lytic replication of -and -herpesviruses results in disease pathologies, such 37 as varicella and herpes zoster for Varicella-Zoster virus (VZV), cold sores and genital 38 lesions for herpes simplex virus (HSV), and congenital defects for cytomegalovirus 39 (CMV). In comparison, malignancies associated with -herpesvirus infection are linked to 40 viral latency. Viral genes expressed during latency promote...

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CD4 T Cells Specific for a Latency-Associated γ-Herpesvirus Epitope Are Polyfunctional and Cytotoxic

Cited by 18 publications

References 44 publications

TCR gene-modified T cells can efficiently treat established hepatitis C-associated hepatocellular carcinoma tumors

TCR gene-modified T cells can efficiently treat established hepatitis C-associated hepatocellular carcinoma tumors

NKG2C/E Marks the Unique Cytotoxic CD4 T Cell Subset, ThCTL, Generated by Influenza Infection

Deletion of immune evasion genes provides an effective vaccine design for tumor-associated herpesviruses

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