Dr. Judy Lieberman, a renowned pediatric professor at Harvard, and Dr. Caroline Junqueira, a visiting scientist and malaria expert from the Oswaldo Cruz Foundation, delve into the fascinating role of γδ T cells in combating Plasmodium infections. They discuss how these unique immune cells function against malaria, their evolution, and their implications for vaccine development. The conversation also touches on broader themes of immune responses, aging, and the intricate balance of inflammation in health and disease.
Gamma-delta T-cells play a significant role in directly killing malaria-infected red blood cells through their recognition of specific metabolites from Plasmodium falciparum.
The study of pyroptosis illustrates how certain viruses exploit host cell mechanisms to induce inflammatory cell death as a defense strategy against infections.
Investigating immune senescence in mice reveals how DNA repair deficiencies lead to poorer immune responses and highlights the link between aging and immune health.
Deep dives
Gamma-Delta T-Cells and Plasmodium Infection
Gamma-delta T-cells play a crucial role in suppressing Plasmodium falciparum infection by directly killing infected red blood cells. These cells, previously thought to be primarily involved in adaptive immunity, have demonstrated the ability to recognize and eliminate malaria-infected cells through contact-dependent mechanisms. Their activation involves recognition of specific metabolites produced by the parasite, enabling the formation of an immunological synapse. This finding expands the understanding of gamma-delta T-cells as versatile immune players capable of both direct killing and potential phagocytosis of pathogens.
Mechanisms of Pyroptosis Induction by Viruses
The induction of pyroptosis, a type of programmed cell death, is initiated by viral infections that inhibit protein synthesis in host cells. Specific viruses such as VSV and HSV1 exploit this mechanism by targeting essential guard proteins that, when inhibited, trigger a cascade leading to pyroptosis. Research showed that gasdermin E, a protein linked to this process, can be cleaved to promote inflammatory cell death, a response that the host utilizes to counteract viral infections. Understanding these pathways sheds light on potential therapeutic targets to enhance immune responses during viral infections.
The Impact of Immune Aging
Research has revealed that artificially aging the immune system in mice significantly accelerates senescence and negatively impacts immune responses. The study focused on knocking out a specific enzyme crucial for DNA repair in hematopoietic cells, leading to increased oxidative damage and robust signs of aging in the immune system. These aged immune cells exhibit reduced responsiveness to antigens and a decline in both T-cell and B-cell populations, resulting in impaired immune function. The findings highlight the interconnectedness of immune senescence and overall organ health, suggesting that aging of immune cells can have systemic effects.
Dendritic Cell Function in Thymic Development
A novel study demonstrated that specific dendritic cells transport microbial antigens from the intestine to the thymus and contribute to the expansion of microbiota-specific T-cells. This discovery emphasizes the role of dendritic cells beyond traditional antigen presentation, illustrating their capacity to influence T-cell development in the thymus. The research found that this process is vital for maintaining gut immunity and suggests that young mice benefit from this mechanism, while adult mice lack this dendritic cell functionality. This added insight could inform future research into therapeutic strategies for enhancing immune responses to gut microbiota.
Inflammation and Antibodies in Severe COVID-19
A recent investigation into severe COVID-19 cases uncovered a correlation between high titers of anti-SARS-CoV-2 antibodies and inflammatory responses in macrophages. These antibodies, particularly characterized by altered glycosylation patterns, were shown to activate the immune response excessively, leading to increased inflammation and lung damage. The study proposed the use of an existing small molecule inhibitor as a potential treatment to mitigate these unwanted immune responses in critically ill patients. This research highlights the fine balance between protective immunity and pathogenesis in COVID-19, pointing to the need for targeted therapeutic strategies.
Dr. Judy Lieberman is a Professor of Pediatrics at Harvard Medical School and holds an Endowed Chair in Cellular and Molecular Medicine at Boston Children’s Hospital. Dr. Caroline Junqueira is an Investigator at the Oswaldo Cruz Foundation and a visiting scientist at Harvard Medical School. Their recent research focuses on the role of γδ T cells in malaria.
How Viruses Cause Pyroptosis – Bcl-2 members MCL-1 and BCL-xL sense translation inhibition during viral infection, leading to Gasdermin E-dependent pyroptosis.
Aging the Immune System – Researchers selectively deleted Ercc1, which encodes a crucial DNA repair protein, to increase senescence in the immune systems of mice, leading to systemic aging.
Thymic Development of Microbiota-Specific T Cells – Scientists showed that intestinal colonization in early life leads to the trafficking of microbial antigens from the intestine to the thymus by intestinal dendritic cells, which then induce the expansion of microbiota-specific T cells.
Antibody-Dependent Inflammation in COVID-19 – Researchers found that in patients with severe COVID-19, high titers and low fucosylation of anti-spike IgG leads to excessive inflammatory responses by alveolar macrophages.
Photo Reference: Courtesy of Drs. Judy Lieberman and Caroline Junqueira
