CD4⁺ T Cell Memory in Malaria and Visceral Leishmaniasis

Protective immunity to chronic parasitic infections such as malaria and visceral leishmaniasis (VL) depends on the generation, maintenance and functional programming of long-lived CD4⁺ T cell memory. Malaria and VL represent two distinct paradigms of immunity. In malaria, protection against severe disease (clinical immunity) develops relatively quickly in endemic populations, even though sterilising immunity is acquired slowly and often remains incomplete1. In contrast, most individuals infected with Leishmania donovani, a causative agent of VL, remain asymptomatic, with only a minority (~one in nine in India), progressing to clinical disease 2. This suggests that a single exposure to Leishmania can generate durable immune responses that prevent disease progression, although sterilising immunity is rare 3, 4. Instead, asymptomatic or drug-treated individuals often harbor persistent parasites yet effectively control infection through long-lived CD4+ T cell–mediated responses, a phenomenon termed concomitant immunity 5, 6. Leveraging these contrasting immune trajectories provides a powerful framework to dissect the development and maintenance of long-lived, protective CD4⁺ T cell responses. Understanding how CD4⁺ T cell memory is formed, maintained, and functionally remodelled in these settings is a critical barrier to developing more effective vaccines and host-directed therapies.

References:

1. Boyle, M.J., Engwerda, C.R. & Jagannathan, P. The impact of Plasmodium-driven immunoregulatory networks on immunity to malaria. Nat Rev Immunol (2024).
2. Singh, O.P., Hasker, E., Boelaert, M. & Sundar, S. Elimination of visceral leishmaniasis on the Indian subcontinent. Lancet Infect Dis 16, e304-e309 (2016).
3. Costa-da-Silva, A.C. et al. Immune Responses in Leishmaniasis: An Overview. Trop Med Infect Dis 7 (2022).
4. Rossi, M. & Fasel, N. How to master the host immune system? Leishmania parasites have the solutions! Int Immunol 30, 103-111 (2018).
5. Stanley, A.C. & Engwerda, C.R. Balancing immunity and pathology in visceral leishmaniasis. Immunology and cell biology 85, 138-147 (2007).
6. Yazdanbakhsh, M. & Sacks, D.L. Why does immunity to parasites take so long to develop? Nat Rev Immunol 10, 80-81 (2010).

This project will investigate how CD4⁺ T cell memory develops in malaria and VL, and how inflammatory cues shape memory cell fate and protective capacity. Using samples from controlled human malaria infection (CHMI) studies, well-established pre-clinical mouse models of malaria and VL, and cutting-edge single-cell multi-omics (scRNA-seq, scTCR-seq, and spatial transcriptomics), students will help define memory-associated CD4⁺ T cell states. The project will also examine how inflammatory mediators and host-directed immunomodulation influence CD4⁺ T cell memory quality, durability, and recall responses.

Students will gain hands-on training in advanced immunology techniques (spectral flow cytometry, antigen-specific T cell assays, single-cell sequencing analysis) and work with unique human clinical samples and translational infection models. The outcomes will provide fundamental insight into how protective CD4⁺ T cell memory is established during parasitic infection and identify strategies to improve vaccine durability and therapeutic immune modulation for malaria and VL.