IL-10 production differentially influences the magnitude, quality, and protective capacity of Th1 responses depending on the vaccine platform

Darrah, Patricia A.; Hegde, Sonia T.; Patel, Dipti T.; Lindsay, Ross; Chen, Linda; Roederer, Mario; Seder, Robert A.

doi:10.1084/jem.20092532

Cited by 80 publications

(65 citation statements)

References 35 publications

(68 reference statements)

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“…These and other studies indicate that unabated proinflammatory signals lead to terminal-effector differentiation and immune exhaustion. Seen in this context, STAT3 signals might facilitate the survival/ transition of high-affinity T cells into long-lived memory T cells, as has been demonstrated in both mouse and human (16,19,(51)(52)(53). In our system, IL-27, signaling through STAT3, would serve as the immunological restraint, critically dampening the higher perceived signal within the higher-affinity T-cell clones.…”

Section: Discussionmentioning

confidence: 62%

IL-27 is required for shaping the magnitude, affinity distribution, and memory of T cells responding to subunit immunization

Pennock

Gapin

Kedl

2014

Proc. Natl. Acad. Sci. U.S.A.

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An elusive goal of cellular immune vaccines is the generation of large numbers of antigen-specific T cells in response to subunit immunization. A broad spectrum of cytokines and cell-surface costimulatory molecules are known to shape the programming, magnitude, and repertoire of T cells responding to vaccination. We show here that the majority of innate immune receptor agonistbased vaccine adjuvants unexpectedly depend on IL-27 for eliciting CD4 + and CD8 + T-cell responses. This is in sharp contrast to infectious challenge, which generates T-cell responses that are IL-27-independent. Mixed bone marrow chimera experiments demonstrate that IL-27 dependency is T cell-intrinsic, requiring T-cell expression of IL-27Rα. Further, we show that IL-27 dependency not only dictates the magnitude of vaccine-elicited T-cell responses but also is critical for the programming and persistence of high-affinity T cells to subunit immunization. Collectively, our data highlight the unexpected central importance of IL-27 in the generation of robust, high-affinity cellular immune responses to subunit immunization.

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Section: Discussionmentioning

confidence: 62%

IL-27 is required for shaping the magnitude, affinity distribution, and memory of T cells responding to subunit immunization

Pennock

Gapin

Kedl

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…As it is associated with greater susceptibility to Leishmania infection in BALB/c mice (Launois et al, 2007), a Th2 response must be avoided when using a LACK vaccine strategy in this strain. Conversely, the Th1 response protects against leishmaniasis (Darrah et al, 2007(Darrah et al, , 2010. Th1 immune responses were triggered by MVA-LEO38-LACK and MVA-LEO160-LACK, with clear differences in magnitude and polyfunctionality.…”

Section: Discussionmentioning

confidence: 99%

“…CD4 T-cells have a crucial role in mediating protection against a variety of pathogens such as human immunodeficiency virus (HIV), influenza, Plasmodium falciparum and Leishmania (Darrah et al, 2007;Reece et al, 2004;Román et al, 2002;Younes et al, 2003). In man and in mouse models of Leishmania major infection, multifunctional T-helper type 1 (Th1) CD4 T-cells correlate with vaccine-mediated protection (Darrah et al, 2010;Macedo et al, 2012). It is nevertheless unclear whether it is possible to potentiate antigenspecific CD4 T-cell responses by inducing heterologous early antigen expression during VACV infection.…”

Section: Introductionmentioning

confidence: 99%

Modification of promoter spacer length in vaccinia virus as a strategy to control the antigen expression

Pilato

Sánchez-Sampedro

Mejías-Pérez

et al. 2015

Journal of General Virology

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Vaccinia viruses (VACVs) with distinct early promoters have been developed to enhance antigen expression and improve antigen-specific CD8 T-cell responses. It has not been demonstrated how the length of the spacer between the coding region of the gene and its regulatory early promoter motif influences antigen expression, and whether the timing of gene expression can modify the antigen-specific CD4 T-cell response. We generated several recombinant VACVs based on the attenuated modified vaccinia Ankara (MVA) strain, which express GFP or the Leishmania LACK antigen under the control of an optimized promoter, using different spacer lengths. Longer spacer length increased GFP and LACK early expression, which correlated with an enhanced LACK-specific memory CD4 and CD8 T-cell response. These results show the importance of promoter spacer length for early antigen expression by VACV and provide alternative strategies for the design of poxvirus-based vaccines.

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“…Multifunctional T cells have been associated with better clinical outcomes of patients infected with human immunodeficiency virus (HIV), 51 reduced HIV replication 52 and protection elicited against smallpox by priming with vaccinia virus 53 . However, the strongest evidence to date for the importance of multifunctional CD4 + T cells in eliciting a protective immune response is in the mouse model of Leishmania major infection 48 , 54 . Therefore, further studies with influenza vaccines are needed to characterise the potential importance of multifunctional T cells in influenza infection.…”

Section: Discussionmentioning

confidence: 99%

The mucosal and systemic immune responses elicited by a chitosan‐adjuvanted intranasal influenza H5N1 vaccine

Svindland

Jul-Larsen

Pathirana

et al. 2011

Influenza Resp Viruses

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Please cite this paper as: Svindland et al. The mucosal and systemic immune responses elicited by a chitosan‐adjuvanted intranasal influenza H5N1 vaccine. Influenza and Other Respiratory Viruses DOI:10.1111/j.1750‐2659.2011.00271.x. Background Development of influenza vaccines that induce mucosal immunity has been highlighted by the World Health Organisation as a priority (Vaccine 2005;23:1529). Dose‐sparing strategies and an efficient mass‐vaccination regime will be paramount to reduce the morbidity and mortality of a future H5N1 pandemic. Objectives This study has investigated the immune response and the dose‐sparing potential of a chitosan‐adjuvanted intranasal H5N1 (RG‐14) subunit (SU) vaccine in a mouse model. Methods Groups of mice were intranasally immunised once or twice with a chitosan (5 mg/ml)‐adjuvanted SU vaccine [7·5, 15 or 30 μg haemagglutinin (HA)] or with a non‐adjuvanted SU vaccine (30 μg HA). For comparison, another group of mice were intranasally immunised with a whole H5N1 (RG‐14) virus (WV) vaccine (15 μg HA), and the control group consisted of unimmunised mice. Results The chitosan‐adjuvanted SU vaccine induced an immune response superior to that of the non‐adjuvanted SU vaccine. Compared with the non‐adjuvanted SU group, the chitosan‐adjuvanted SU vaccine elicited higher numbers of influenza‐specific antibody‐secreting cells (ASCs), higher concentrations of local and systemic antibodies and correspondingly an improved haemagglutination inhibition (HI) and single radial haemolysis (SRH) response against both the homologous vaccine strain and drifted H5 strains. We measured a mixed T‐helper 1/T‐helper 2 cytokine response in the chitosan‐adjuvanted SU groups, and these groups had an increased percentage of virus‐specific CD4+ T cells producing two Thelper 1 (Th1) cytokines simultaneously compared with the non‐adjuvanted SU group. Overall, the WV vaccine induced higher antibody concentrations in sera and an HI and SRH response similar to that of the chitosan‐adjuvanted SU vaccine. Furthermore, the WV vaccine formulation showed a stronger bias towards a T‐helper 1 profile than the SU vaccine and elicited the highest frequencies of CD4+ Th1 cells simultaneously secreting three different cytokines (INFγ+, IL2+ and INFα+). As expected, two immunisations gave a better immune response than one in all groups. The control group had very low or not detectable results in the performed immunoassays. Conclusion The cross‐clade serum reactivity, improved B‐ and T‐cell responses and dose‐sparing potential of chitosan show that a chitosan‐adjuvanted intranasal influenza vaccine is a promising candidate vaccine for further preclinical development.

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IL-10 production differentially influences the magnitude, quality, and protective capacity of Th1 responses depending on the vaccine platform

Cited by 80 publications

References 35 publications

IL-27 is required for shaping the magnitude, affinity distribution, and memory of T cells responding to subunit immunization

IL-27 is required for shaping the magnitude, affinity distribution, and memory of T cells responding to subunit immunization

Modification of promoter spacer length in vaccinia virus as a strategy to control the antigen expression

The mucosal and systemic immune responses elicited by a chitosan‐adjuvanted intranasal influenza H5N1 vaccine

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