Main idea: Numerous studies have shown that vaccination in older adults over the age of 65 is largely ineffective, which is believed to be due to an age-related decline in immune system functionality known as immunosenescence. It is suggested that one of the potential causes of the onset and maintenance of immunosenescence in the body is Myeloid-Derived Suppressor Cells (MDSCs), a heterogeneous population of pathologically activated monocytes and granulocytes with a unique metabolic and genetic profile. These cells have gained significant attention due to their ability to induce both systemic and local immunosuppression, as well as to promote the accumulation of other immunosuppressive cells, such as T-regulatory cells. The negative role of MDSCs in inhibiting specific T-cell antitumor immunity has been convincingly demonstrated in cancer, both experimentally and in clinical settings. The number of studies showing the involvement of these cells in the development of chronic inflammation, both infectious and non-infectious, is rapidly increasing. A number of experimental works suggest that MDSCs may negatively affect the development of anti-infective adaptive immunity. This study is dedicated to investigating the role of MDSCs in regulating the adaptive immune response to anti-infective vaccines in an experiment with aged animals and developing approaches to enhance vaccination effectiveness by pharmacologically suppressing the immunosuppressive activity of these cells.
The aim of the project is to evaluate the role of MDSCs in suppressing the immune response to vaccines during aging in an experimental setting and to develop pharmacological methods to enhance vaccine efficacy.
Objectives:
1) To evaluate the dynamics of MDSC content and their functional characteristics in immunized old mice compared to young mice.
2) To assess the antigen-specific immune response in immunized old mice relative to young mice.
3) To examine the ability of MDSCs to suppress antigen-specific T cell responses in old mice under in vitro conditions.
4) To investigate the mechanisms by which myeloid-derived suppressor cells suppress antigen-specific immune responses in vaccinated old mice under in vitro conditions.
5) To study the effect of vitamin D administration (or other agents that suppress MDSC activity) on the development of humoral and cellular immune responses to vaccines in old animals, in relation to MDSC activity in these animals.
The following conclusions have been drawn based on the obtained results:
1 Aging is accompanied by the accumulation of CD11b+ Gr1+ cells characterized by reduced expression of the F4/80 marker and the ability to effectively inhibit both mitogen-induced and antigen-specific activity of autologous T cells. Subpopulation analysis demonstrated an increased level of granulocytic, but not monocytic, MDSC subpopulations in old mice compared to young animals.
2 In old mice from both inbred and outbred strains, a decrease in the proportion of the total CD3+ T cell population and the proportion of T cells expressing the adhesion marker CD62L was observed. A significant inverse correlation between the proportion of MDSC and the number of CD62L+ T cells was found, which may suggest a mechanism of suppression of effector T cell activity via proteolytic cleavage of this molecule by MDSC, resulting in the inability of naïve T cells to migrate to secondary lymphoid organs.
3 Vaccination of mice with whole-virion SARS-CoV-2 and a commercial influenza vaccine led to the production of specific antibodies, with no difference in antibody titers observed between young and old animals. This indicates that the increased MDSC fraction is not associated with impairments in the antibody response to the immunogens used. Vaccination with whole-virion SARS-CoV-2 and the commercial influenza vaccine did not affect the proportion of CD11b+ Gr1+ myeloid cells, dendritic cells (DCs), or T cells in either young or old animals.
4 Calcitriol administration did not affect specific antibody production in old vaccinated animals, which may suggest that vitamin D does not influence the ability of mice to produce an antigen-specific response to the antigenic stimulus. However, animals receiving calcitriol exhibited increased antigen-specific production of IFN-γ by T cells in response to immunogen stimulation in vitro.
- Calcitriol administration significantly increased the content of F4/80-expressing CD11b+ Gr1+ cells in old mice, suggesting polarization of myeloid cells towards macrophages.
Publications
Publications for the year 2023:
1) Абдусаттарова Ю.Р., Әбен Д.С., Абдолла Н., Тдеулиева Р.Т. Кали А., Перфильева Ю.В. Эффективность вакцинации от COVID-19 у пожилых людей// Вестник КАЗНМУ. – 2023. – №2 (65). – С.59-82.
2) Әбен Д.С., Перфильева Ю.В., Абдолла Н., Кали А., Тлеулиева Р.Т., Лушова А.В., Абдусаттарова Ю. Р. Оценка антиген-специфического ответа B- и T-клеток у разновозрастных мышей при иммунизации против COVID-19//Фундаментальные и прикладные исследования в области молекулярной биологии, биохимии, биотехнологии: мат-лы междунар. науч. конф. молодых ученых. – Алматы, 2023. – С. 64.
3) Абдусаттарова Ю. Р., Перфильева Ю.В., Кали А., Тлеулиева Р.Т., Әбен Д.С., Лушова А.В., Абдолла Н. Исследование возможной ассоциации между уровнем MDSC и антиген-специфической продукцией IFNCD4 Т-клетками//Фундаментальные и прикладные исследования в области молекулярной биологии, биохимии, биотехнологии: мат-лы междунар. науч. конф. молодых ученых. – Алматы, 2023. – С. 63.
Publications for the year 2024:
4) Ostapchuk Y., Lushova A., Kan S., Abdolla N., Kali A., Tleulieva R., Perfilyeva A., Perfilyeva Y. Long-term changes in the phenotype and cytokine production of monocytes in COVID-19 recovered and vaccinated individuals//Infection and Immunity.– 2024. – N.92:e00216-24. doi: 10.1128/iai.00216-24. (JCI QUARTILE – Q2 (Infectious diseases); JCI PERCENTILE – 50.78 (Infectious diseases) Web of Science; CiteScore 2023 = 6, Parasitology 82% Scopus).
5) Perfilyeva Y, Aquino A., Borodin M., Kali A., Abdolla N., Ostapchuk Y., Tleulieva R, Perfilyeva A, Jainakbayev N., Sharipov K., Belyaev N. Can interventions targeting MDSCs improve the outcome of vaccination in vulnerable populations?//International Reviews of Immunology. – 2024. – N.21. – P.1-17. (JIF QUARTILE – Q2 (Immunology); JIF PERCENTILE – 58.1 (Immunology) Web of Science; CiteScore 2023 = 11, Immunology and Allergy 82% Scopus).
6) Перфильева Ю.В., Абдолла Н., Кали А., Тлеулиева Р.Т., Әбен Д.С., Абдусаттарова Ю.Р., Лушова А.В., Остапчук Е.О., Каральник Б.В., Беляев Н.Н. Миелоидные супрессорные клетки (MDSC) регулируют Т-клеточный ответ у старых мышей, иммунизированных цельновирионной вакциной SARS-CoV-2//Eurasian Journal of Applied Biotechnology. – 2024, – Vol.1. – C. 53-61. doi: 10.11134/btp.1.2024.5. (журнал рекомендован КОКСНВО МНВО РК).
Note – Representative dot plots of flow cytometry (A) and summarized data with mean ± SD (B and C) are presented. The statistical significance of differences between groups is indicated as *p < 0.05, ** p < 0.005 (Mann-Whitney test). MJ – young animals, SJ – old animals, MVJ – young vaccinated animals, SVJ – old vaccinated animals.
Figure 1: MDSC levels in old and young BALB/c mice (A and B) and CD1 (C) before vaccination (SJ and MJ) and 7-14 days after administration of the booster dose of vaccine (SVJ and MVJ).
Note – Summarized data with mean ± SD (A) and representative flow cytometry dot plots (B) are shown.
Figure 2: Production of IFNγ and TNFα by CD3+ T cells from old immunized CD1 lineage mice without stimulation (U/s) and in response to the addition of concanavalin A (ConA), Influvac, specific (P/v), and control (P/v control) peptides to splenocyte culture in the presence of Gr1+ cells at different ratios.