Understanding the Plasmodium berghei liverstage specific CD8 T cells maintenance and role in liver damage

Abstract

Whole parasite vaccine (WPV) approaches provide sterile protection against malaria to the host by restricting the parasite at liver-stage. However, host does not maintain protection for long because of waning parasite-induced memory CD8+ T (TM) cell responses. Significant proportion of TM cells are cytotoxic in nature which might cause damage to liver cells (auto-reactivity), while interacting through MHC-I/TCR, whereas liver in order to maintain the homeostasis can induce death in these cells, a reason for waning of CD8+ T cell responses and hence protection in mice. Therefore, we wanted to find-out whether TM cells are auto-reactive in nature or not. Another possibility could be that the TM cells might not be getting the adequate survival signals for long-term maintenance. IL-15 dependence of protection in mice depicts other factor(s) either are additionally required or are negatively influencing the maintenance of TM cells. There are reports showing requirement of self-peptide MHC-I/TCR interaction for survival of memory CD8+ T cells. Therefore, we wanted to explore the influence of self-MHC-I/TCR (SMT) interaction in maintenance of TM cells. Moreover, regulatory T (Treg) cells and inhibitory receptor (CTLA-4) also shown to have an important role in long-term maintenance of memory cells through maintaining quiescence. Therefore, we also looked for the presence of Treg cells and expression of inhibitory receptor (CTLA-4) by T cells in parasite immunized mice. newlineTo address the above issues we have adopted RAS (radiation attenuated sporozoite), a WPV approach. For determining the self-damaging/auto-reactive nature of TM cells we performed liver histology and serum ALT assay at various time points post RAS immunization. We observed normal liver histology as well as ALT level around day 80 post last immunization depicting the non-damaging/non-auto-reactive nature of TM cells. Further, we explored whether SMT interaction has any role in the maintenance of TM. Previously, we have shown that TM cells in mice immunized with RAS are differentially maintained from that of mice challenged with infectious sporozoite that correlates with the longevity of protection. Here, we found that TM cells of challenge group mice would be having better survival capability as they show lesser Annexin V reactivity, higher Bcl-2 expression and their potential to undergo homeostatic proliferation is superior. Thus, it could be inferred that TM cells would be better maintained in challenge group mice, which coincide with their longer protection period. newline