Gradual Decline in Malaria-Specific Memory T Cell Responses Leads to Failure to Maintain Long-Term Protective Immunity to Plasmodium chabaudi AS Despite Persistence of B Cell Memory and Circulating Antibody

Abstract

The mechanisms responsible for the generation and maintenance of immunological memory to Plasmodium are poorly understood and the reasons why protective immunity in humans is so difficult to achieve and rapidly lost remain a matter for debate. A possible explanation for the difficulty in building up an efficient immune response against this parasite is the massive T cell apoptosis resulting from exposure to high-dose parasite Ag. To determine the immunological mechanisms required for long-term protection against P. chabaudi malaria and the consequences of high and low acute phase parasite loads for acquisition of protective immunity, we performed a detailed analysis of T and B cell compartments over a period of 200 days following untreated and drug-treated infections in female C57BL/6 mice. By comparing several immunological parameters with the capacity to control a secondary parasite challenge, we concluded that loss of full protective immunity is not determined by acute phase parasite load nor by serum levels of specific IgG2a and IgG1 Abs, but appears to be a consequence of the progressive decline in memory T cell response to parasites, which occurs similarly in untreated and drug-treated mice with time after infection. Furthermore, by analyzing adoptive transfer experiments, we confirmed the major role of CD4+ T cells for guaranteeing long-term full protection against P. chabaudi malaria.

Type I interferons suppress CD4+ T‐cell‐dependent parasite control during blood‐stage Plasmodium infection

“…Thus, one implication of our findings is that transient blockade of IFN-I during vaccination against blood-stage malaria could induce a quantitatively improved T-cell response. Given the likely importance of longlived CD4 1 T-cell memory in sustained immunity to blood-stage infection [6], our data identify IFN-I as a novel target for modulation in order to improve CD4 1 T-cell-dependent, vaccineinduced immunity to blood-stage malaria.…”

“…Blood-stage malaria vaccines developed in mice to promote CD4 1 T-cell-dependent immunity can control hyperparasitemia [5]. However, protection is rarely complete, and wanes over time as T-cell memory dissipates [6]. Thus, improving parasite-specific CD4 1 T-cell responses might improve immunity to blood-stage malaria.…”

Evaluating antidisease immunity to malaria and implications for vaccine design

“…As well as the problem of antigenic diversity and clonal variation on the parasites’ side, the past decade has led to the identification of several ‘faults’ that may explain why antibodies are slowly acquired, and not adequately induced in younger children. A few notable mechanisms include (i) the identification of a subset of memory B cells called ‘atypical’ memory B cells, which are inefficient at secreting antibodies25, 26 (ii) the inefficient acquisition of long‐lived plasma cells26, 27, 28, 29 (iii) the induction of an exhausted phenotype of helper T cells30, 31 and (iv) the delay in germinal centre development during infection 32, 33. Given that a vaccine, particularly blood stage vaccine candidates, would potentially rely upon an efficient humoral immune response for effectiveness in children, it is imperative to understand how malaria infection elicits these mechanisms, and possibly address whether or not an antiparasite vaccine would be successful.…”

IFN-γ–Induced Priming Maintains Long-Term Strain-Transcending Immunity against Blood-Stage Plasmodium chabaudi Malaria

“…with 5 3 10 8 mature iRBCs. Blood samples were collected at 1 h intervals and stained with SYTO16 (Molecular Probes, Life Technologies) as described previously (22 Parasite-specific ELISA PcAS-specific IgG1 and IgG2a serum levels were quantified by ELISA as described elsewhere (15). Briefly, 96-well flat-bottom microtest plates (Costar) were coated overnight (4˚C) with a total PcAS extract (10 mg/ml).…”

“…On the basis of this finding, it has been suggested that sustained exposure to malarial Ags is required not only for the generation of memory and effector cells but also for their maintenance (14). In fact, the partial loss of protective immunity to homologous challenge observed after elimination of reminiscent parasitemia is related to a decline in the CD4 + memory T (T M ) cell response to parasites (15). Although much is known about how innate immune recognition affects adaptive immune responses, the role of adaptive immune cells in shaping the innate immune system is largely unexplored.…”