DS0402 - Améliorer la Santé par la médecine personnalisée, le diagnostic, la prévention et la thérapie, les stratégies palliatives, en concevant le vivant dans son environnement

Priming T cell responses in old age – PriCelAge

Priming T cell responses in old age

Life expectancy in France has almost doubled over the last century. However, the elderly have a high rate of severe infections, autoimmune diseases or cancer compared to younger subjects. This is certainly linked to the immune system decline with age. Alterations in the ability to induce an immune response may also explain the reduced efficacy of vaccination in the elderly.

Altered naïve T cell compartment with advanced age

Cellular immunity, mediated by T lymphocytes, is very important for the host response to various pathogens and cancers. The naive T cell compartment is essential because it is the basis for the induction of T cell responses. Our hypothesis is that quantitative and qualitative alterations of naive T cells play a key role in the immune system defects associated with advanced age. The objectives of this project are to conduct a full characterization of naive T cells in the elderly (> 75 years), including their ability to induce cell responses de novo.

To this end, we are setting up state-of-the-art immunological analytical approaches, to generate relevant information on the quantitative and qualitative characteristics of naive T cells from blood samples. In particular, using an in vitro approach developed in the lab, we will directly test the effect of potential additives that might favour the induction of T cell responses in elderly populations.

Our results show already reduced capacities of activation, proliferation and differentiation into effector cells of naive CD8+ T lymphocytes from the elderly.

Eventually, we will try to find ways to improve the ability to induce de novo cell responses in the elderly, in order to define strategies to boost the effectiveness of vaccination in this population.
In sum, our understanding of the decline of immune competence with advanced age in humans supports the development of new diagnostic tools and the execution of clinical trials to improve immunization and adjuvant formulation.

Lissina A, Briceño O, Afonso G, Larsen M, Gostick E, Price DA, Mallone R, Appay V. Priming of Qualitatively Superior Human Effector CD8+ T Cells Using TLR8 Ligand Combined with FLT3 Ligand. J Immunol. 2016 Jan 1;196(1):256-63.

Briceño O, Lissina A, Wanke K, Afonso G, von Braun A, Ragon K, Miquel T, Gostick E, Papagno L, Stiasny K, Price DA, Mallone R, Sauce D, Karrer U, Appay V. Reduced naïve CD8+ T-cell priming efficacy in elderly adults. Aging Cell. 2016 Feb;15(1):14-21.

Alanio C, Nicoli F, Sultanik P, Flecken T, Perot B, Duffy D, Bianchi E, Lim A, Clave E, van Buuren MM, Schnuriger A, Johnsson K, Boussier J, Garbarg-Chenon A, Bousquet L, Mottez E, Schumacher TN, Toubert A, Appay V, Heshmati F, Thimme R, Pol S, Mallet V, Albert ML. Bystander hyperactivation of preimmune CD8+ T cells in chronic HCV patients. Elife. 2015 Nov 14;4.

Although the news that life expectancy in France has nearly doubled over the last century is a reflection of the positive impact of medical knowledge and disease control, there is a consequent burden to society. Elderly people have an increased rate of severe infection, autoimmune disease or cancer as compared to younger individuals, resulting in a significant reduction in their quality of life and ever increasing medical costs. Disease in the elderly is likely related to an age-related decline of the immune system homeostasis. Growing evidence indicates that advanced age is indeed associated with a variety of phenotypic and functional alterations of the cells and organs of the immune system, referred to as immune aging or immunosenescence. Alterations of the ability to respond to new antigens may explain the reduced vaccine efficacy observed in old people. This project is predicated on the belief that understanding immune aging is a public health priority, with broad implications in prevention of infectious diseases, and optimization of vaccine efficacy in the elderly.

Cellular immunity, which is mediated by CD8+ and CD4+ T cells, is critically important in the host response to various pathogens, and the control of cells undergoing malignant transformation. However, with increasing age, the T cell compartment is biased towards increasing proportions of highly differentiated oligoclonal memory populations, with short telomeres and limited proliferative capacity, considered to be approaching replicative senescence. There is also evidence that aging compromises the functional capacity of dendritic cells. Together, these age-related changes may limit the capacity of the cellular immunity to effectively mount responses specific to new antigenic determinants, such as those associated with emerging strains of influenza virus or emerging tumor cells. Although it is clear that detectable antigen-specific T cells can be induced safely in humans by vaccination, the challenge is now to improve vaccine immunogenicity and efficacy in elderly.

The naïve T cell compartment represents the primary resource for the induction of T cell responses. Although it is established that age-related thymic involution is associated with a reduced production in naïve T cells, the precise attributes of naïve T cells themselves in elderly remain largely uncharacterized. Our hypothesis is that the quantitative and qualitative decline of the naïve T cell compartment with advanced age results in a suboptimal capacity to prime effective antigen specific T cell responses. The objectives of our project are therefore to perform a comprehensive characterization of naïve CD8+ and CD4+ T cells in the elderly, and thymectomized young adults who present evidence of premature aging, examining ways to improve the initiation of de novo T cell responses – ultimately helping to define strategies aimed at enhancing the efficacy of T cell based vaccination in these populations. To this end, we propose to apply original and state-of-the-art analytical approaches, currently developed by our groups, to generate relevant information on the quantitative and qualitative attributes of naïve CD8+ and CD4+ T cells and their ability to mount effective T cell responses from blood samples. We will directly test the effect of potential adjuvants that could favor the induction of T cell responses in the targeted populations. Additionally, our optimized immune monitoring strategies will be assessed for their use as in vitro diagnostic tools that can support future vaccine studies. Our combined expertise will ensure efficient translation of cutting-edge immunologic concepts. In sum, our understanding of the decline of immune competence with advanced age in humans will support the development of new diagnostic tools and the execution of clinical studies to improve vaccination and adjuvant formulation.

Project coordinator

Monsieur Victor Appay (Institut national de la santé et de la recherche médicale)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INSERM Institut national de la santé et de la recherche médicale
AP-HP Assistance publique - Hôpitaux de Paris
INSERM Institut national de la santé et de la recherche médicale
INSERM Inserm

Help of the ANR 509,889 euros
Beginning and duration of the scientific project: December 2014 - 36 Months

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