Early Activation of Lung CD8+ T Cells After Immunization with Live Plasmodium berghei Malaria Sporozoites.

Abstract

Background: Two novel malaria vaccines, RTS,S and R21, mark a significant step forward in malaria research, but eradication demands vaccines with higher efficacy. Recent trials using late-arresting genetically attenuated parasites (LA-GAP) highlight their effectiveness as next-generation vaccines, likely through CD8⁺ T-cell activation targeting late liver-stage parasites. However, the distribution of LA-GAP-activated T cells in different organs that culminate towards high-level protection in the liver remains unclear.

Methods: This study aimed to map immune responses in the livers and lungs of mice immunized with LA-GAP, shedding light on the role of different organs in priming T-cell responses towards immunity.

Results: Particularly in the lungs we found an impressive increase of CD8⁺, double negative T cells (5%), γδ (2.5%), effector memory CD8⁺ T cells (46%), and tissue resident memory CD8⁺ T cells (3%). These lung T cells are highly activated (expressing CD11c, Ki67, KLRG1) and exhibited 4-fold higher Granzyme A expression and significant TNF⁺ cell increases as compared to their liver counterparts (10.2% vs 2.6%). These differences start already at the early 2-day timepoint at which time the lungs show an impressive 10.2% increase in TNF⁺ CD8⁺ T cells, whereas the liver shows a more modest increase of 2.6% of these cells.

Conclusion: These findings highlight the lungs as a crucial site for immune priming and T-cell activation, underscoring the need for further investigation of organ-specific responses to fully understand the potential of LA-GAP immunization as a powerful strategy in the fight against malaria.