Infectious nature of Plasmodium berghei sporozoite modulates APCs to induce better liver stage memory CD8 T cells

Abstract

Developing effective anti-malarial vaccine has been a challenge. Vaccination with radiation-attenuated sporozoites (RAS) or genetically-attenuated sporozoites (GAP) has shown to confer complete sterile protection against Plasmodia liver-stage (LS) infection that lasts about six to nine months in mice. We have found that the intermittent infectious sporozoite (Inf. Spz) challenge to immune mice following RAS vaccination extends the longevity of sterile protection by maintaining CD8+T cell memory responses to LS infection. In the present study, we observed that a specialized population of dendritic cells (DCs), known for antigen cross-presentation, accumulates in the liver of mice that received Inf. Spz at a frequency that is at least three times higher. Our results are consistent with the others as CD8and#61537;+DCs increased in number in the livers of mice immunized with RAS or GAP. As the accumulation of CD8and#61537;+DCs in the liver was thought to be a result of migration of the same from circulation, the expression of chemokines (Ccl-20 and Ccl-21) in the liver of mice was measured. The prominent expression of chemokines in liver of mice inoculated with Inf. Spz. suggestive of the fact that greater accumulation of CD8and#61537;+DCs at the site of infection is because of the infectious status of the sporozoite. newlineFurther, the capacity of DCs to modulate T cells is predominantly dependent on their activation status, which involves the up-regulation of major-histocompatibility (MHCs) and elevated expression of costimulatory molecules (CD80, CD86, and CD40) on the surface of DCs. Therefore, we studied the role of infectious status of sporozoites in modulating CD8and#61537;+DCs. Our results, in fact, suggest that expression level of MHCs and co-stimulatory molecules significantly induced by Inf. Spz meet the requirements for better T cell activation and memory formation. Similarly, CD40-CD40L signalling is known to be involved in cross presentation and APC licensing to promote survival of antigen specific CD8+T cells. Therefore, Inf. Spz inoculation/challenge that enhances not only the accumulation of CD8and#61537;+DCs in the liver, but also favored generation of higher frequencies of activated CD4+T cells with greater expression of CD40L. This in turn might promote APC licensing of CD8and#61537;+DCs and provide help to CD8+T cells. The expression of CD40 or CD40L on CD8+T cells promoted by Inf. Spz challenge provides us a plausible explanation that CD8+T cells, either receive signals from the licensed CD8and#61537;and#61483;DCs through CD40-CD40L or from CD4+T cells through CD40L-CD40 or from both to become a qualitatively better LS memory CD8+T cells newline