Dengue fever, a mosquito-borne virus infection, is a growing global health crisis, with India at its epicentre. In 2024 alone, health agencies reported over 14 million cases worldwide, with more than 10,000 dengue-related fatalities. Despite its widespread prevalence in over 100 countries—70% of cases occurring in Asia—critical questions remain unanswered. Why do some individuals experience only mild symptoms while others develop life-threatening complications? Why do some individuals produce weak or even harmful antibodies, making them more susceptible to severe disease? One of the most perplexing aspects of dengue immunity is Antibody-Dependent Enhancement (ADE)—a phenomenon where low-quality antibodies inadvertently assist the virus in spreading, rather than offering protection. This knowledge gap has been a major hurdle in the development of safe and effective vaccines.
A multi-centre study led by Dr Nimesh Gupta’s group at the BRIC-National Institute of Immunology has now shed light on a previously unknown aspect of how humans respond to the dengue virus. The study has identified a new immune pathway with profound implications for vaccine development. This discovery is particularly relevant for India, where dengue outbreaks are becoming more frequent and severe, and multiple dengue vaccine candidates are currently under development.
The group investigated the contribution of CD4+ T cells to B cell responses in human dengue infection. By analyzing dengue patients and healthy humans from the dengue-affected region, the research team identified a dominant peripheral T cell subset that accumulates in severe patients and could induce B cell differentiation and antibody generation, via an interleukin-21 (IL-21)-related pathway.
Key findings of the study are—
● Based on the single-cell insights, the study marked these cells as a unique IL21+ T-cell subset.
● These IL-21+ T cells are found in higher numbers in patients with severe dengue.
● Instead of providing protection, they drive an excessive and uncontrolled antibody response, leading to immune system over-activation and potentially worsening the disease.
● Human lymphoid tissue studies showed that these immune cells migrate beyond the bloodstream
to lymph nodes and potentially peripheral tissues, further impacting immune function and disease
progression.
This discovery shifts focus to how T cells regulate B cells, uncovering IL-21+ T cells as key drivers of
severe dengue. Using single-cell technology, researchers identified this subset’s role in harmful immune
over-activation. The findings pave the way for early prediction of severe cases, improved vaccine design,
and targeted therapies to prevent life-threatening complications.
With dengue cases rising yearly, India urgently needs scientific breakthroughs to combat the disease. This discovery marks a major leap forward in understanding dengue immunity, laying the foundation for
better diagnostics, more effective vaccines, and life-saving treatments.
Reference:
Ansari, A., Sachan, S., Ahuja, J., Venkadesan, S., Nikam, B., Kumar, V., Jain, S., Singh, B. P., Coshic, P., Sikka, K., Wig, N., Sette, A., Weiskopf, D., Mohanty, D., Soneja, M., & Gupta, N. (2025). Distinct features of a peripheral T helper subset that drives the B cell response in dengue virus infection. Cell reports, 115366. Advance online publication. https://doi.org/10.1016/j.celrep.2025.115366