Polyfunctional CD4+ T Cell Responses to Immunodominant Epitopes Correlate with Disease Activity of Virulent Salmonella

Maybeno, Matt; Redeker, Anke; Welten, Suzanne P. M.; Peters, Bjoern; Loughhead, Scott; Schoenberger, Stephen P.; Sette, Alessandro; Arens, Ramon

doi:10.1371/journal.pone.0043481

Cited by 23 publications

(24 citation statements)

References 60 publications

(70 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Triple positive transgenic cells expressed significantly higher levels of IFNγ per cell compared with single- or double-positive cells (Fig. 4F), as previously described for pathogen-specific polyfunctional T cells in other models of infection (4, 8, 48). Triple positive cells also expressed significantly higher levels of TNF per cell compared to TNF monofunctional cells, but at a reduced magnitude (60% increase), and no differences were observed in IL-2 GMFI (data not shown).…”

Section: Resultssupporting

confidence: 83%

A Chlamydia-Specific TCR-Transgenic Mouse Demonstrates Th1 Polyfunctionality with Enhanced Effector Function

Poston

Girardi

et al. 2017

The Journal of Immunology

View full text Add to dashboard Cite

Chlamydia is responsible for millions of new infections annually, and current efforts focus on understanding cellular immunity for targeted vaccine development. The Chlamydia-specific CD4 T cell response is characterized by the production of IFNγ, and polyfunctional Th1 responses are associated with enhanced protection. A major limitation in studying these responses is the paucity of tools available for detection, quantification, and characterization of polyfunctional, antigen-specific T cells. We addressed this problem by developing a TCR transgenic mouse with CD4 T cells that respond to a common antigen in Chlamydia muridarum and Chlamydia trachomatis. Using an adoptive transfer approach, we show that naïve transgenic CD4 T cells become activated, proliferate, migrate to the infected tissue, and acquire a polyfunctional Th1 phenotype in infected mice. Polyfunctional Tg Th1 effectors demonstrated enhanced IFNγ production compared to polyclonal cells, protected immune deficient mice against lethality, mediated bacterial clearance, and orchestrated an anamnestic response. Adoptive transfer of Chlamydia-specific CD4 TCR Tg T cells with polyfunctional capacity offers a powerful approach for analysis of protective effector and memory responses against chlamydial infection, and demonstrates that an effective monoclonal CD4 T cell response may successfully guide subunit vaccination strategies.

show abstract

Section: Resultssupporting

confidence: 83%

A Chlamydia-Specific TCR-Transgenic Mouse Demonstrates Th1 Polyfunctionality with Enhanced Effector Function

Poston

Girardi

et al. 2017

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…We have reported that CD4 T cells from exposed individuals respond to FliC, although responses were not different between healthy seropositive donors and those recovering from clinical melioidosis (7). Multiple CD4 T cell epitopes have been identified in FliC from Salmonella in the setting of murine and human infection (30). The dual properties of Pseudomonas flagellin as an immunodominant antigen and a strong TLR5 agonist make it in some respects a candidate vaccine immunogen in the context of Pseudomonas aeruginosa infections (31).…”

Section: Discussionmentioning

confidence: 99%

CD4+ T Cell Epitopes of FliC Conserved between Strains of Burkholderia: Implications for Vaccines against Melioidosis and Cepacia Complex in Cystic Fibrosis

Musson

Reynolds

Rinchai

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

Burkholderia pseudomallei (Bp), is the causative agent of melioidosis, characterized by pneumonia and fatal septicemia and prevalent in SE Asia. Related Burkholderia species are strong risk factors of mortality in cystic fibrosis (CF). The Bp flagellar protein FliC is strongly seroreactive and vaccination protects challenged mice. We assessed Bp FliC peptide binding affinity to multiple HLA class II alleles, then assessed CD4 T cell immunity in HLA class II transgenic mice and in seropositive individuals in Thailand. T cell hybridomas were generated to investigate cross-reactivity between Bp and the related Burkholderia species associated with Cepacia Complex CF. Bp FliC contained several peptide sequences with ability to bind multiple HLA class II alleles. Several peptides were shown to encompass strong CD4 T cell epitopes in Bp-exposed individuals and in HLA transgenic mice. In particular, the p38 epitope is robustly recognized by CD4 T cells of seropositive donors across diverse HLA haplotypes. T cell hybridomas against an immunogenic Bp FliC epitope also cross-reacted with orthologous FliC sequences from B. multivorans and B. cenocepacia, important pathogens in CF. Epitopes within FliC were accessible for processing and presentation from live or heat-killed bacteria, demonstrating that flagellin enters the HLA class II antigen presentation pathway during infection of macrophages with B. cenocepacia. Collectively, the data support the possibility of incorporating FliC T cell epitopes into vaccination programs targeting both at-risk individuals in Bp endemic regions as well as CF patients.

show abstract

“…In the case of Salmonella, it is clear that CD4 T cells are essential, whereas CD8 T cells appear to be dispensable (18)(19)(20)56). The case for humoral immunity is somewhat more complicated.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, it will be worthwhile to assess the possibility that CD4 T cell epitopes such as the one described in our study may be capable not only of providing a prophylactic intervention but also of being used to intervene during infection. Along these lines, a recent study showed that immunization with a combination of three novel MHC-II peptides from S. Typhimurium was able to lower the bacterial burdens of infected mice even during infection (56).…”

Section: Discussionmentioning

confidence: 99%

Vaccination with a Single CD4 T Cell Peptide Epitope from a Salmonella Type III-Secreted Effector Protein Provides Protection against Lethal Infection

et al. 2014

View full text Add to dashboard Cite

Salmonella infections affect millions worldwide and remain a significant cause of morbidity and mortality. It is known from mouse studies that CD4 T cells are essential mediators of immunity against Salmonella infection, yet it is not clear whether targeting CD4 T cell responses directly with peptide vaccines against Salmonella can be effective in combating infection. Additionally, it is not known whether T cell responses elicited against Salmonella secreted effector proteins can provide protective immunity against infection. In this study, we investigated both of these possibilities using prime-boost immunization of susceptible mice with a single CD4 T cell peptide epitope from Salmonella secreted effector protein I (SseI), a component of the Salmonella type III secretion system. This immunization conferred significant protection against lethal oral infection, equivalent to that conferred by whole heat-killed Salmonella bacteria. Surprisingly, a well-characterized T cell epitope from the flagellar protein FliC afforded no protection compared to immunization with an irrelevant control peptide. The protective response appeared to be most associated with polyfunctional CD4 T cells raised against the SseI peptide, since no antibodies were produced against any of the peptides and very little CD8 T cell response was observed. Overall, this study demonstrates that eliciting CD4 T cell responses against components of the Salmonella type III secretion system can contribute to protection against infection and should be considered in the design of future Salmonella subunit vaccines.

show abstract

Polyfunctional CD4+ T Cell Responses to Immunodominant Epitopes Correlate with Disease Activity of Virulent Salmonella

Cited by 23 publications

References 60 publications

A Chlamydia-Specific TCR-Transgenic Mouse Demonstrates Th1 Polyfunctionality with Enhanced Effector Function

A Chlamydia-Specific TCR-Transgenic Mouse Demonstrates Th1 Polyfunctionality with Enhanced Effector Function

CD4+ T Cell Epitopes of FliC Conserved between Strains of Burkholderia: Implications for Vaccines against Melioidosis and Cepacia Complex in Cystic Fibrosis

Vaccination with a Single CD4 T Cell Peptide Epitope from a Salmonella Type III-Secreted Effector Protein Provides Protection against Lethal Infection

Contact Info

Product

Resources

About