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Immunization with radiation-attenuated Plasmodium sporozoites (RAS) induces sterile and long-lasting protective immunity. Although intravenous (IV) route of RAS immunization is reported to induce superior immunity compared to intradermal (ID) injection, its role in the maintenance of sterile immunity is yet to be understood. We investigated whether the route of homologous sporozoite challenge of Plasmodium berghei (Pb) RAS-immunized mice would influence the longevity of protection. C57BL/6 mice immunized with Pb-RAS by IV were 100% protected upon primary IV/ID sporozoite challenge. In contrast, ID immunization resulted in 80% protection, regardless of primary challenge route. Interestingly, the route of primary challenge was found to bring difference in the maintenance of sterile protection. While IV Pb RAS-immunized mice remained protected at all challenges regardless of the route of primary challenge, ID Pb-RAS-immunized mice receiving ID primary challenge became parasitaemic upon secondary IV challenge. Significantly, primary IV challenge of Pb RAS ID-immunized mice resulted in 80% and 50% survival at secondary and tertiary challenges, respectively. According to phenotypically diverse liver CD8 + T cells, the percentages and the numbers of both CD8 + T effector memory and resident memory cells were significantly higher in IV than in ID Pb RAS-immunized mice. IFN-γ-producing CD8 + T cells specific to Pb TRAP 130 and MIP-4-Kb-17 were also found significantly higher in IV mice than in ID mice. The enhanced T-cell generation and the longevity of protection appear to be dependent on the parasite load during challenge when infection is tolerated under suboptimal CD8 + T-cell response., (© 2019 John Wiley & Sons Ltd.)

Inducing long-lived memory T cells by sub-unit vaccines has been a challenge. Subunit vaccines containing single immunogenic target antigen from a given pathogen have been designed with the presumption of mimicking the condition associated with natural infection, but fail to induce quality memory responses. In this study, we have included non-target antigens with vaccine candidate, OVA, in the inoculum containing TLR ligands to suffice the minimal condition of pathogen to provoke immune response. We found that inclusion of immunogenic HEL (hen egg lysozyme) or poorly immunogenic MBP (Myelin Basic protein) non-target antigen enhances the OVA specific CD4 T cell responses. Interestingly, poorly immunogenic MBP was found to strongly favor the generation of OVA specific memory CD4 T cells. MBP not only improves magnitude of T cell response but also promotes the T cells to undergo higher cycles of division, one of the characteristic of central memory T cells. Inclusion of MBP with vaccine targets was also found to promote multiple cytokine producing CD4 T cells. We also found that challenge of host with non-target antigen MBP favors generation of central Memory T cells., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Immunization with radiation-attenuated sporozoites (RAS) shown to confer complete sterile protection against Plasmodia liver-stage (LS) infection that lasts about 6 to 9 months in mice. We have found that the intermittent infectious sporozoite challenge to immune mice following RAS vaccination extends the longevity of sterile protection by maintaining CD8 + T cell memory responses to LS infection. It is reported that CD8α + dendritic cells (DCs) are involved in the induction of LS-specific CD8 + T cells following RAS or genetically attenuated parasite (GAP) vaccination. In this study, we demonstrate that CD8α + DCs respond differently to infectious sporozoite or RAS inoculation. The higher accumulation and activation of CD8α + DCs was seen in the liver in response to infectious sporozoite 72 h postinoculation and found to be associated with higher expression of chemokines (CCL-20 and CCL-21) and type I interferon response via toll-like receptor signaling in liver. Moreover, the infectious sporozoites were found to induce qualitative changes in terms of the increased MHCII expression as well as costimulatory molecules including CD40 on the CD8α + DCs compared to RAS inoculation. We have also found that infectious sporozoite challenge increased CD40L-expressing CD4 + T cells, which could help CD8 + T cells in the liver through "licensing" of the antigen-presenting cells. Our results suggest that infectious sporozoite challenge to prior RAS immunized mice modulates the CD8α + DCs, which might be shaping the fate of memory CD8 + T cells against Plasmodium LS infection.

Radiation attenuated sporozoite (RAS), a whole‐parasite vaccine approach, provides sterile protection against malaria. However, RAS immunization does not confer protection for long, and that has been correlated with the waning parasite–induced memory CD8+ T‐cell responses. Interestingly, an intermittent infectious (wild type) sporozoite challenge to the RAS‐vaccinated mice lengthened the protection period from 6 to 18 months. Herein, we have studied the changes induced by the infectious sporozoites in RAS‐induced memory CD8+ T cells for conferring lengthened protection. We observed that the infectious sporozoite challenge boosted the frequency of foreign antigen–experienced memory CD8+ T cells. In those CD8+ T cells, it has reduced the Annexin‐V reactivity, raised Bcl‐2 expression, and also more cells undergo homeostatic proliferation (Ki‐67+). It has also scaled down the frequency of Nur77 and CX3CR1 high expressing cells in those memory CD8+ T‐cell populations which we further correlated with better survival signals. [ABSTRACT FROM AUTHOR]

The significance of self-peptide-MHC-I/TCR (SMT) interaction in the survival of CD8+ T cells during naïve- and developmental-stages is well documented. However, the same for the memory stage is contentious. Previous studies have attempted to address the issue using MHC-I or TCR deficient systems, but inconsistent findings with memory CD8+ T cells of different TCR specificities have complicated the interpretation. Differential presence and/or processing of TCR-signals downstream in memory CD8+ T cells of different TCR specificities could be thought of as a reason. In this study, we examined the TCR-signals downstream in memory CD8+ T cells and compared them to the presence of survival-related signals (Annexin-V, Bcl-2, and Ki-67). We categorically tracked foreign antigen-experienced memory CD8+ T (TM) cells generated after Plasmodium pre-erythrocytic-stage malaria infection in C57BL/6 mice. Interestingly, we found that memory CD8+ T cells had more TCR-signals downstream than naive cells. We reasoned and attributed the increased expression of cell adhesion molecules to the enhanced TCR-signaling. TCR-signals downstream correlate more closely with survival signals in naive CD8+ T cells than with death signals in TM cells. Further investigation using antigen-specific CD8+ T cells and diverse infection systems would aid in conceptualizing the findings. [ABSTRACT FROM AUTHOR]