The Survival of Memory CD8 T Cells That Is Mediated by IL-15 Correlates with Sustained Protection Against Malaria

Abstract

Ag-specific memory T cell responses elicited by infections or vaccinations are inextricably linked to long-lasting protective immunity. Studies of protective immunity amongst residents of malaria endemic areas indicate that memory responses to Plasmodia antigens are not adequately developed or maintained, as persons who survive episodes of childhood malaria are still vulnerable to either persistent or intermittent malaria infections. In contrast, multiple exposures to radiation-attenuated Plasmodia sporozoites (γ-spz) induce long-lasting protective immunity to experimental sporozoite challenge. We previously demonstrated that sterile protection induced by Plasmodium berghei (Pb) γ-spz is MHC-class I-dependent and CD8 T cells are the key effectors. IFN-γ+CD8 T cells that arise in Pb γ-spz immunized B6 mice are found predominantly in the liver and are sensitive to levels of liver-stage Ag depot and they express CD44hiCD62Llo markers indicative of effector/effector memory (E/EM) phenotype. The developmentally related central memory (CM) CD8 T cells express elevated levels of CD122 (IL-15Rβ), which suggests that CD8 TCM cells depend upon IL-15 for maintenance. Using IL-15 deficient mice, we demonstrate here that although protective immunity is inducible in these mice, protection is short-lived, mainly owing to the inability of CD8 TCM cells to survive in the IL-15 deficient milieu. We present a hypothesis consistent with a model whereby intrahepatic CD8 TCM cells, being maintained by IL-15-mediated survival and basal proliferation, are conscripted into CD8 TE/EM cell pool during subsequent infections.

Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15

“…We cannot, therefore, determine a correlation between the numbers of CD8 In transgenic mouse models or severe combined immunodeficiency models of alloreactivity, it has been previously suggested that IL-7 and IL-15 favors the generation of central-memory and "T-memory stem cells." 26,[28][29][30] We found that IL-7 and IL-15 can also significantly enrich for the CD8…”

Imaging Plasmodium immunobiology in the liver, brain, and lung

“…Rodent malaria models suggest that CD8+ effector memory T cells play a central role in the elimination of Plasmodium infected hepatocytes from the liver [101-104]. Immunization with attenuated sporozoites generates a reservoir of hepatic CD8+ T cells, which is maintained by KC and DC derived IL-15 in the presence of a depot of parasite LS antigens, and that resident CD44 hi CD45RB hi CD122 hi CD62L lo/hi CD8+ central memory T cells are required for the proliferation of IFN-γ producing CD44 hi CD45RB lo CD122 lo CD62L lo effector memory T (T EM ) cells capable of conferring protection against reinfection [104-107]. In vitro studies have shown that P. berghei and P. yoelii specific CD8+ T cells are capable of contact-dependent recognition of parasite antigen on the surface of infected hepatocytes and elimination of LS in the absence of cytokines such as IFN-γ or TNF-α [108-110].…”

TAP‐mediated processing of exoerythrocytic antigens is essential for protection induced with radiation‐attenuated Plasmodium sporozoites

“…While CD8 + T EM cells are the main producers of IFN-γ, CD8 + T CM cells form a reservoir of Ag-specific cells needed for the maintenance of long-term protective immunity [40]. We asked whether immunization of TAP −/− mice with P. berghei RAS would also induce differentiation of liver CD8 + T cells.…”