Dominance and Diversity in the Primary Human CD4 T Cell Response to Replication-Competent Vaccinia Virus

Jing, Lichen; Chong, Tiana M.; Byrd, Benjamin; McClurkan, Christopher L.; Huang, Jay; Story, Brian T.; Dunkley, Karissa M.; Aldaz-Carroll, Lydia; Eisenberg, Roselyn J.; Cohen, Gary H.; Kwok, William W.; Sette, A; Koelle, David M.

doi:10.4049/jimmunol.178.10.6374

Cited by 36 publications

(60 citation statements)

References 94 publications

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“…Culture medium changes were done biweekly for 3 weeks. To raise bulk cultures of VV-specific CD4 T cells, we either used the CD137 staining method detailed above and sorted live, CD4 ϩ , CD8 Ϫ , and CD137 ϩ cells in bulk and stimulated them identically or alternatively stimulated whole PBMC with UV-treated vaccinia virus and supported proliferation with IL-2 as described previously (16).…”

Section: Methodsmentioning

confidence: 99%

“…Bulk VV-specific CD4 T-cell cultures expanded from PBMC were interrogated with both genomic library-based and full-length ORF methods as described previously (16,17). Molecular truncations were made to detect short antigenic viral polypeptides in initial hits (16,17).…”

Section: Methodsmentioning

confidence: 99%

“…Separately, we used published (16,17) methods to define VV CD4 T-cell antigens, and then epitopes, for participant V9. In preliminary work, a VVreactive bulk CD4 T-cell line from this subject recognized 23 VV polypeptides (not shown).…”

Section: Cd137 Upregulation Identifies Virus-specific Cd4 T Cellsmentioning

confidence: 99%

See 2 more Smart Citations

CD4 T-Cell Memory Responses to Viral Infections of Humans Show Pronounced Immunodominance Independent of Duration or Viral Persistence

Jing

Schiffer

Chong

et al. 2013

J Virol

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Little is known concerning immunodominance within the CD4 T-cell response to viral infections and its persistence into longterm memory. We tested CD4 T-cell reactivity against each viral protein in persons immunized with vaccinia virus (VV), Immunodominance refers to the proportion of T cells specific for a defined epitope in relation to the entire set of T cells reacting to a complex antigen (1). For infectious pathogens encoding many polypeptides, the immunodominance of an open reading frame (ORF) is the proportion of the total pathogen-specific response accounted for by T cells reacting with this ORF. Immunoprevalence is a related concept, referring to the proportion of a population responding to an immunogen (2). The CD8 T-cell response to complex microbes can show remarkably strong immunodominance in humans and inbred animals.As antigen processing differs between T-cell subsets, it is not clear that immunodominance also applies to CD4 T-cell responses. For VV, memory CD4 T-cell responses in inbred mice are quite polyclonal and do not exhibit dominance. The top 14 epitopes account for only 20% of the total VV-specific CD4 T-cell response (3). Data for the human CD4 T-cell response to cytomegalovirus, in contrast, were somewhat consistent with immunodominance. Subjects recognized a median of 12 ORFs per person (of 213 ORFs studied), with the top 6 ORFs accounting for about 40% of the overall response (4). In humans, HLA variation is expected to influence the identity of immunodominant and immunoprevalent antigens in specific individuals. Model systems have identified additional factors controlling epitope choice for CD4 T cells, including naïve T-cell repertoire (5), antigen abundance (6), antigen folding (7), protease processing and epitopeflanking regions (8), and antigenic competition (9).Vaccinia virus is an orthopoxvirus that causes an infection that resolves completely in several weeks in immunocompetent hosts. CD4 T-cell memory persists for decades despite the absence of antigen reexposure, but little is known about the detailed architecture of long-term memory. The monotonic decline of specific antibody levels supports lack of intermittent boosting (10). VV has over 200 ORFs, so each human has a myriad of potential CD4 reactive T-cell specificities. Herpes simplex virus 1 (HSV-1) also has a complex proteome, but in contrast to self-limited VV infections, HSV-1 infections are chronic with intermittent reactivations. Following initial epithelial replication, the virus establishes persistence in the innervating sensory ganglia. Intermittent reactivation of latent HSV-1 in essentially all HSV-1-infected persons (11) results in periodic viral antigen exposure to HSV-1-specific memory T cells (12).To determine the breadth and persistence of CD4 T-cell immunodominance in acute and chronic human viral infections, we compared patterns of CD4 T-cell immunodominance between recent and remote VV recipients. The immune responses of persons chronically infected with HSV-1 were also investigated as an example of a c...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

CD4 T-Cell Memory Responses to Viral Infections of Humans Show Pronounced Immunodominance Independent of Duration or Viral Persistence

Jing

Schiffer

Chong

et al. 2013

J Virol

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“…Vaccinia strain WR was grown and titered as described previously (76). Viral antigens for CD4 + cell stimulation and readout assays were diluted sonicates of Vero (HSV-1) or BSC40 (vaccinia) harvested by scraping when 80%-100% of the monolayer showed cytopathic effect and treated with UV light to eliminate infectious virus (72,77). HeLa and Cos-7 cells (ATCC) were cultured in DMEM.…”

Section: Methodsmentioning

confidence: 99%

Cross-presentation and genome-wide screening reveal candidate T cells antigens for a herpes simplex virus type 1 vaccine

Jing¹,

Haas²,

Chong³

et al. 2012

J. Clin. Invest.

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161

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Herpes simplex virus type 1 (HSV-1) not only causes painful recurrent oral-labial infections, it can also cause permanent brain damage and blindness. There is currently no HSV-1 vaccine. An effective vaccine must stimulate coordinated T cell responses, but the large size of the genome and the low frequency of HSV-1-specific T cells have hampered the search for the most effective T cell antigens for inclusion in a candidate vaccine. We have now developed what we believe to be novel methods to efficiently generate a genome-wide map of the responsiveness of HSV-1-specific T cells, and demonstrate the applicability of these methods to a second complex microbe, vaccinia virus. We used cross-presentation and CD137 activation-based FACS to enrich for polyclonal CD8 + T effector T cells. The HSV-1 proteome was prepared in a flexible format for analyzing both CD8 + and CD4 + T cells from study participants. Scans with participant-specific panels of artificial APCs identified an oligospecific response in each individual. Parallel CD137-based CD4 + T cell research showed discrete oligospecific recognition of HSV-1 antigens. Unexpectedly, the two HSV-1 proteins not previously considered as vaccine candidates elicited both CD8 + and CD4 + T cell responses in most HSV-1-infected individuals. In this era of microbial genomics, our methods -also demonstrated in principle for vaccinia virus for both CD8 + and CD4 + T cells -should be broadly applicable to the selection of T cell antigens for inclusion in candidate vaccines for many pathogens. IntroductionHerpes simplex virus type 1 (HSV-1) infects 60% of the US population and has a significant cumulative health care burden in addition to causing painful recurrent oral-labial infections. For example, brain and eye infections can cause permanent damage or blindness (1). HSV-1 also causes approximately 50% of clinical first-episode genital herpes in the United States. Vaccines for HSV that have been tested thus far have failed in clinical trials, including a recent phase III trial of an adjuvanted glycoprotein D (gD2) product (2). This vaccine elicits antibody and CD4 + T cell responses but fails to induce CD8 responses. Newer platforms can elicit CD8 + and CD4 + cells, but they require rationally selected T cell antigens. We therefore developed methods to permit measurement of both CD8 and CD4 responses to the complete HSV-1 proteome to begin rational prioritization of next-generation vaccine candidates.Several recent observations support the concept that an effective HSV vaccine will need to induce coordinated CD8 + and CD4 + T cell responses. HSV-1-specific CD8 + T cells localize to the site of HSV-1 infection in human and murine trigeminal ganglia (TG) (3-5), and both HSV-specific CD8 + and CD4 + T cells localize to acute and healed sites of skin infection in mice and humans, sug-

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“…Major epitopes are therefore carried by different peptides and, as suggested by recent investigations in mice, may result from size variation of the naive precursor repertoire (37). Variation in epitope hierarchy was also reported in vaccinated donors (38). Altogether, we suggest introducing in a peptide vaccine at least the peptides 17-31, 90 -104, 96 -110, and 128 -142, which are major epitopes and hence are expected to elicit a strong response in each donor.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of HLA-DR- and HLA-DP4-Restricted CD4+ T Cell Response Specific for the Tumor-Shared Antigen Survivin in Healthy Donors and Cancer Patients

Wang

Kerzerho

Adotévi

et al. 2008

The Journal of Immunology

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Because of the wide distribution of the survivin Ag in a variety of tumors, we have investigated the survivin-specific CD4+ T cell response in healthy donors and cancer patients. Screening of the entire sequence of survivin for HLA class II binding led to the identification of seven HLA-DR promiscuous peptides, including four HLA-DP4 peptides. All of the peptides were able to prime in vitro CD4+ T cells of eight different healthy donors. The peptide-specific T cell lines were stimulated by dendritic cells loaded with the recombinant protein or with the lysates of tumor cells. The high frequency of responders (i.e., immunoprevalence) was provided by a wide reactivity of multiple peptides. Six peptides were T cell stimulating in at least half of the donors and were close to CD8+ T cell epitopes. HLA-DR molecules were more frequently involved in T cell stimulation than were HLA-DP4 molecules, and hence immunoprevalence relies mainly on HLA-DR promiscuity in the survivin Ag. In two cancer patients a spontaneous CD4+ T cell response specific for one of these peptides was also observed. Based on these observations, the tumor-shared survivin does not appear to be the target of immune tolerance in healthy donors and cancer patients and is a relevant candidate for cancer vaccine.

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Dominance and Diversity in the Primary Human CD4 T Cell Response to Replication-Competent Vaccinia Virus

Cited by 36 publications

References 94 publications

CD4 T-Cell Memory Responses to Viral Infections of Humans Show Pronounced Immunodominance Independent of Duration or Viral Persistence

CD4 T-Cell Memory Responses to Viral Infections of Humans Show Pronounced Immunodominance Independent of Duration or Viral Persistence

Cross-presentation and genome-wide screening reveal candidate T cells antigens for a herpes simplex virus type 1 vaccine

Comprehensive Analysis of HLA-DR- and HLA-DP4-Restricted CD4+ T Cell Response Specific for the Tumor-Shared Antigen Survivin in Healthy Donors and Cancer Patients

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