Article

The adjuvant effect of TLR agonists on CD4+ effector T cells is under the indirect control of regulatory T cells

Department of Immunology, Paris, France.
European Journal of Immunology (Impact Factor: 4.52). 08/2011; 41(8):2303-13. DOI: 10.1002/eji.201041387
Source: PubMed

ABSTRACT TLR agonists have been suggested to directly impact Tregs, thereby enhancing or reversing their suppressive function. Here, in order to select TLR agonists leading to potent effector T-cell responses, while minimizing Treg inhibitory function, we used a model antigen, covalently linked to an inert delivery system, combined with a large panel of TLR agonists, for the immunization of mice with an attenuated/depleted or intact Treg subset. We observed that the negative modulation of effector CD4(+) T cells exerted by Tregs cannot be circumvented, whatever the TLR agonist used as adjuvant. To better understand the impact of TLR agonists on Tregs, we investigated (i) the TLR expression profile of highly purified CD4(+) Foxp3(+) Tregs, at steady state or subsequent to in vivo activation by TLR agonists and (ii) the Treg phenotype after in vivo and in vitro activation by TLR agonists. Our results demonstrate that TLR agonists, as single signal inducers, are not able to directly activate Tregs. The phenotypic Treg activation observed in vivo, following TLR administration, does not result from cross-talk with conventional T cells but is rather a consequence of the interaction with other immune cell type(s).

0 Followers
 · 
114 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The development of effective vaccines against life-threatening pathogens in human diseases represents one of the biggest challenges in biomedical science. Vaccines traditionally make use of the body's own immune armoury to combat pathogens. Yet, while our immune system is mostly effective in eliminating or controlling a diverse range of microorganisms, its responses are incomplete or somewhat limited in several other cases. How immune responses are restrained during certain infections has been a matter of debate for many years. The discovery of regulatory T cells (Tregs), an immune cell type that plays a central role in maintaining immune homeostasis and controlling appropriate immune responses, has shed light into many questions. Indeed, it has been proposed that while Tregs might be beneficial in preventing excessive tissue damage during infection, they might also favour pathogen persistence by restraining effector immune responses. In addition, Tregs are believed to limit immune responses upon vaccination. Different strategies have been pursued to circumvent Treg activity during immunization, but the lack of specific tools for their study has led sometimes to controversial conclusions. With the advent of novel mouse models that allow specific depletion and/or tracking of Treg populations in vivo, novel aspects of Treg biology during infection have been unravelled. In this review, we describe the new advances in understanding Treg biology during infection and evaluate Treg depletion as a novel adjuvant strategy for vaccination.
    Microbial Biotechnology 09/2011; 5(2):260-9. DOI:10.1111/j.1751-7915.2011.00299.x · 3.21 Impact Factor
  • Encyclopedia of Biomedical Polymers and Polymeric Biomaterials, 01/2013: chapter Aliphatic Polyesters: Particulate Vaccine Delivery; Taylor and Francis Group..
  • [Show abstract] [Hide abstract]
    ABSTRACT: Antitumor immunity is strongly influenced by the balance of tumor antigen-specific effector and regulatory T cells. However, the impact that vaccine adjuvants have in regulating the balance of antigen-specific T cell populations is not well understood. We found that antigen-specific T regulatory cells (Treg) were induced following subcutaneous vaccination with either OVA or melanoma-derived peptides, with a restricted expansion of effector T cells. Addition of the adjuvants CpG-ODN or Poly(I:C) preferentially amplified effector T cells over Tregs, dramatically increasing the antigen-specific T effector:Treg ratios and inducing polyfunctional effector cells. In contrast, two other adjuvants, imiquimod and Quil A saponin, favored an expansion of antigen-specific Tregs and failed to increase effector T cell:Treg ratios. Following therapeutic vaccination of tumor-bearing mice, high ratios of tumor-specific effector T cells:Tregs in draining lymph nodes were associated with enhanced CD8+ T cell infiltration at the tumor site and a durable rejection of tumors. Vaccine formulations of peptide+CpG-ODN or Poly(I:C) induced selective production of pro-inflammatory Type I cytokines early after vaccination. This environment promoted CD8+ and CD4+ effector T cell expansion over that of antigen-specific Tregs, tipping the effector T cell to Treg balance to favor effector cells. Our findings advance understanding of the influence of different adjuvants on T cell populations, facilitating the rational design of more effective cancer vaccines.
    Cancer Research 09/2013; 73(22). DOI:10.1158/0008-5472.CAN-13-0875 · 9.28 Impact Factor