Longitudinal Requirement for CD4+ T Cell Help for Adenovirus Vector–Elicited CD8+ T Cell Responses

Provine, Nicholas M.; Larocca, Rafael A.; Penaloza-MacMaster, Pablo; Borducchi, Erica N.; McNally, Anna; Parenteau, Lily; Kaufman, David R.; Barouch, Dan H.

doi:10.4049/jimmunol.1302806

Cited by 25 publications

(33 citation statements)

References 75 publications

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“…This data would suggest that prior reports of reduced antigen clearance CD4 + T cell deficient animals might instead reflect insufficient expansion of an otherwise functional CD8 + T cell response (3–10). In this study, we demonstrate that CD4 + T cells are required at priming for optimal expansion of CD8 + T cell responses by Ad vector and poxvirus vector immunization, consistent with previous reports (13, 20–22). Additionally, we identify a critical role for CD4 + T cells in driving acquisition of CD8 + T cell effector functions and preventing dysfunctional differentiation, in contrast to previous reports showing largely functional primary CD8 + T cell effector responses in the absence of CD4 + T cells (12, 16–19).…”

Section: Discussionsupporting

confidence: 92%

“…This vaccination regimen generates small, but measurable, CD8 + T cell responses in the absence of CD4 + T cell help (13, 20, 21). Mice were depleted of CD4 + T cells by two sequential doses of the αCD4 antibody (clone GK1.5) beginning on the day prior to immunization and CD4 + T cell depletion was maintained by re-administration of the antibody every 21 days.…”

Section: Resultsmentioning

confidence: 99%

“…Following replication-incompetent adenovirus (Ad) vector immunization, unhelped CD8 + T cells fail to express effector phenotype markers (20), and display impaired primary CD8 + T cell expansion (13, 20–22). Viral vector vaccines, including Ad vectors, are being intensively studied as candidate vaccine platforms against an array of pathogens (23–30), and thus represent clinically relevant tools for probing immune regulatory pathways.…”

Section: Introductionmentioning

confidence: 99%

“…These two dysfunctional states represent temporally distinct phenomena and are driven by distinct transcriptional programs (34), but both represent states of T cell hypo-functionality. While atypical differentiation of Ad vector-elicited CD8 + T cells primed without CD4 + T cell help is observed (20), it is unclear when this initially occurs, and how profoundly the functionality of these unhelped cells are altered compared to other well-described states of hypo-functionality. Thus, a more detailed investigation of the timing of when and how CD4 + T cells regulate Ad vector-elicited CD8 + T cell differentiation is required.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Immediate Dysfunction of Vaccine-Elicited CD8+ T Cells Primed in the Absence of CD4+ T Cells

Provine

Larocca

Aïd

et al. 2016

The Journal of Immunology

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CD4+ T cell help is critical for optimal CD8+ T cell memory differentiation and maintenance in many experimental systems. Additionally, many reports have identified reduced primary CD8+ T cell responses in the absence of CD4+ T cell help, which often coincides with reduced antigen or pathogen clearance. Here we demonstrate that absence of CD4+ T cells at the time of adenovirus vector immunization of mice led to immediate impairments in early CD8+ T cell functionality and differentiation. Unhelped CD8+ T cells exhibited a reduced effector phenotype, decreased ex vivo cytotoxicity, and decreased capacity to produce cytokines. This dysfunctional state was imprinted within 3 days of immunization. Unhelped CD8+ T cells expressed elevated levels of inhibitory receptors and exhibited transcriptomic exhaustion and anergy profiles by gene set enrichment analysis. Dysfunctional, impaired effector differentiation also occurred following immunization of CD4+ T cell-deficient mice with a poxvirus vector. This study demonstrates that following priming with viral vectors, CD4+ T cell help is required to promote both the expansion and acquisition of effector functions by CD8+ T cells, which is accomplished by preventing immediate dysfunction.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Immediate Dysfunction of Vaccine-Elicited CD8+ T Cells Primed in the Absence of CD4+ T Cells

Provine

Larocca

Aïd

et al. 2016

The Journal of Immunology

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“…Assessment of Ad5-induced T cell responses has been more focused on CD8 T cells, while relatively less is known about CD4 T cell responses elicited by Ad5 immunization. Previous studies have shown that CD4 T cells are critical for transgenespecific CD8 T cell and antibody responses elicited by Ad vector immunization (7)(8)(9). However, the phenotypic and functional properties of CD4 T cells induced by Ad vectors remain less well investigated.…”

mentioning

confidence: 99%

Adenovirus Serotype 5 Vaccination Results in Suboptimal CD4 T Helper 1 Responses in Mice

Lee

Hashimoto

et al. 2017

J Virol

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Adenovirus serotype 5 (Ad5) is one of the most widely used viral vectors and is known to generate potent T cell responses. While many previous studies have characterized Ad5-induced CD8 T cell responses, there is a relative lack of detailed studies that have analyzed CD4 T cells elicited by Ad5 vaccination. Here, we immunized mice with Ad5 vectors encoding lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) and examined GP-specific CD4 T cell responses elicited by Ad5 vectors and compared them to those induced by an acute LCMV infection. In contrast to LCMV infection, where balanced CD4 T helper 1 (Th1) and T follicular helper (Tfh) responses were induced, Ad5 immunization resulted in a significantly reduced frequency of Th1 cells. CD4 T cells elicited by Ad5 vectors expressed decreased levels of Th1 markers, such as Tim3, SLAM, T-bet, and Ly6C, had smaller amounts of cytotoxic molecules like granzyme B, and produced less interferon gamma than CD4 T cells induced by LCMV infection. This defective CD4 Th1 response appeared to be intrinsic for Ad5 vectors and not a reflection of comparing a nonreplicating vector to a live viral infection, since immunization with a DNA vector expressing LCMV-GP generated efficient CD4 Th1 responses. Analysis at early time points (day 3 or 4) after immunization with Ad5 vectors revealed a defect in the expression of CD25 (interleukin-2 [IL-2] receptor alpha chain) on Ad5-elicited CD4 T cells, and administration of exogenous IL-2 following Ad5 immunization partially restored CD4 Th1 responses. These results suggest that impairment of Th1 commitment after Ad5 immunization could be due to reduced IL-2-mediated signaling.IMPORTANCE During viral infection, generating balanced responses of Th1 and Tfh cells is important to induce effective cell-mediated responses and provide optimal help for antibody responses. In this study, to investigate vaccine-induced CD4 T cell responses, we characterized CD4 T cells after immunization with Ad5 vectors expressing LCMV-GP in mice. Ad5 vectors led to altered effector differentiation of LCMV GP-specific CD4 T cells compared to that during LCMV infection. CD4 T cells following Ad5 immunization exhibited impaired Th1 lineage commitment, generating significantly decreased Th1 responses than those induced by LCMV infection. Our results suggest that suboptimal IL-2 signaling possibly plays a role in reduced Th1 development following Ad5 immunization. KEYWORDS CD4 T cell responses, T helper 1 (Th1), T follicular helper (Tfh), adenovirus serotype 5, vaccination R ecombinant adenovirus (Ad) vectors are one of the most favorable vaccine platforms as they have certain potential advantages, such as strong immunogenicity, large transgene capacity, and good safety profile. Ad-based vaccine vectors can induce

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Adenovirus vector and mRNA vaccines: Mechanisms regulating their immunogenicity

Provine

Klenerman

2022

Eur J Immunol

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Replication‐incompetent adenovirus (Ad) vector and mRNA‐lipid nanoparticle (LNP) constructs represent two modular vaccine platforms that have attracted substantial interest over the past two decades. Due to the COVID‐19 pandemic and the rapid development of multiple successful vaccines based on these technologies, there is now clear real‐world evidence of the utility and efficacy of these platforms. Considerable optimization and refinement efforts underpin the successful application of these technologies. Despite this, our understanding of the specific pathways and processes engaged by these vaccines to stimulate the immune response remains incomplete. This review will synthesize our current knowledge of the specific mechanisms by which CD8 + T cell and antibody responses are induced by each of these vaccine platforms, and how this can be impacted by specific vaccine construction techniques. Key gaps in our knowledge are also highlighted, which can hopefully focus future studies.

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Longitudinal Requirement for CD4+ T Cell Help for Adenovirus Vector–Elicited CD8+ T Cell Responses

Cited by 25 publications

References 75 publications

Immediate Dysfunction of Vaccine-Elicited CD8+ T Cells Primed in the Absence of CD4+ T Cells

Immediate Dysfunction of Vaccine-Elicited CD8+ T Cells Primed in the Absence of CD4+ T Cells

Adenovirus Serotype 5 Vaccination Results in Suboptimal CD4 T Helper 1 Responses in Mice

Adenovirus vector and mRNA vaccines: Mechanisms regulating their immunogenicity

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