T cell-mediated immunity to malaria Kurup, Samarchith P; Butler, Noah S; Harty, John T
Nature reviews. Immunology,
07/2019, Letnik:
19, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Immunity to malaria has been linked to the availability and function of helper CD4
T cells, cytotoxic CD8
T cells and γδ T cells that can respond to both the asymptomatic liver stage and the ...symptomatic blood stage of Plasmodium sp. infection. These T cell responses are also thought to be modulated by regulatory T cells. However, the precise mechanisms governing the development and function of Plasmodium-specific T cells and their capacity to form tissue-resident and long-lived memory populations are less well understood. The field has arrived at a point where the push for vaccines that exploit T cell-mediated immunity to malaria has made it imperative to define and reconcile the mechanisms that regulate the development and functions of Plasmodium-specific T cells. Here, we review our current understanding of the mechanisms by which T cell subsets orchestrate host resistance to Plasmodium infection on the basis of observational and mechanistic studies in humans, non-human primates and rodent models. We also examine the potential of new experimental strategies and human infection systems to inform a new generation of approaches to harness T cell responses against malaria.
Infection of erythrocytes with Plasmodium species induces clinical malaria. Parasite-specific CD4(+) T cells correlate with lower parasite burdens and severity of human malaria and are needed to ...control blood-stage infection in mice. However, the characteristics of CD4(+) T cells that determine protection or parasite persistence remain unknown. Here we show that infection of humans with Plasmodium falciparum resulted in higher expression of the inhibitory receptor PD-1 associated with T cell dysfunction. In vivo blockade of the PD-1 ligand PD-L1 and the inhibitory receptor LAG-3 restored CD4(+) T cell function, amplified the number of follicular helper T cells and germinal-center B cells and plasmablasts, enhanced protective antibodies and rapidly cleared blood-stage malaria in mice. Thus, chronic malaria drives specific T cell dysfunction, and proper function can be restored by inhibitory therapies to enhance parasite control.
The longevity of plasma cells is dependent on their ability to access and reside in so-called niches that are predominantly located in the bone marrow. Here, by employing a traceable method to label ...recently generated plasma cells, we showed that homeostatic plasma cells in the bone marrow and spleen were continuously replenished by newly generated B220hiMHC-IIhi populations that progressively differentiated into B220loMHC-IIlo long-lived plasma cell (LLPC) populations. We also found that, in the bone marrow, germinal center (GC)-independent and GC-dependent plasma cells decayed similarly upon NP-CGG engagement, and both entered the B220loMHC-IIlo LLPC pool. Compared with NP+B220hiMHC-IIhi plasma cells, NP+B220loMHC-IIlo cells were more immobilized in the bone marrow niches and showed better survival potential. Thus, our results suggest that the adhesion status of bone marrow plasma cells is dynamically altered during their differentiation and is associated with provision of survival signals.
Radiation-attenuated Plasmodium sporozoites (RAS) are the only vaccine shown to induce sterilizing protection against malaria in both humans and rodents. Importantly, these "whole-parasite" vaccines ...are currently under evaluation in human clinical trials. Studies with inbred mice reveal that RAS-induced CD8 T cells targeting liver-stage parasites are critical for protection. However, the paucity of defined T cell epitopes for these parasites has precluded precise understanding of the specific characteristics of RAS-induced protective CD8 T cell responses. Thus, it is not known whether quantitative or qualitative differences in RAS-induced CD8 T cell responses underlie the relative resistance or susceptibility of immune inbred mice to sporozoite challenge. Moreover, whether extraordinarily large CD8 T cell responses are generated and required for protection following RAS immunization, as has been described for CD8 T cell responses following single-antigen subunit vaccination, remains unknown. Here, we used surrogate T cell activation markers to identify and track whole-parasite, RAS-vaccine-induced effector and memory CD8 T cell responses. Our data show that the differential susceptibility of RAS-immune inbred mouse strains to Plasmodium berghei or P. yoelii sporozoite challenge does not result from host- or parasite-specific decreases in the CD8 T cell response. Moreover, the surrogate activation marker approach allowed us for the first time to evaluate CD8 T cell responses and protective immunity following RAS-immunization in outbred hosts. Importantly, we show that compared to a protective subunit vaccine that elicits a CD8 T cell response to a single epitope, diversifying the targeted antigens through whole-parasite RAS immunization only minimally, if at all, reduced the numerical requirements for memory CD8 T cell-mediated protection. Thus, our studies reveal that extremely high frequencies of RAS-induced memory CD8 T cells are required, but may not suffice, for sterilizing anti-Plasmodial immunity. These data provide new insights into protective CD8 T cell responses elicited by RAS-immunization in genetically diverse hosts, information with relevance to developing attenuated whole-parasite vaccines.
Chronic viral infections remain a global health concern. The early events that facilitate viral persistence have been linked to the activity of the immunoregulatory cytokine IL-10. However, the ...mechanisms by which IL-10 facilitates the establishment of chronic infection are not fully understood. Herein, we demonstrated that the antigen sensitivity of CD8+ T cells was decreased during chronic infection and that this was directly mediated by IL-10. Mechanistically, we showed that IL-10 induced the expression of Mgat5, a glycosyltransferase that enhances N-glycan branching on surface glycoproteins. Increased N-glycan branching on CD8+ T cells promoted the formation of a galectin 3-mediated membrane lattice, which restricted the interaction of key glycoproteins, ultimately increasing the antigenic threshold required for T cell activation. Our study identified a regulatory loop in which IL-10 directly restricts CD8+ T cell activation and function through modification of cell surface glycosylation allowing the establishment of chronic infection.
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•IL-10 directly increases the threshold for CD8+ T cell activation•Induction of Mgat5 is necessary for IL-10-mediated repression•The galectin-glycoprotein surface lattice promotes T cell dysfunction•Disruption of galectin binding restores T cell function and viral control
The mechanisms by which IL-10 facilitates the establishment of chronic infections are not fully understood. Smith et al. demonstrate that during chronic infections, IL-10 upregulates N-glycan branching on CD8+ T cell surface glycoproteins, which reduces signal transduction downstream of the T cell receptor and decreases CD8+ T cell antigen sensitivity and capacity to control pathogen burden.
Humoral immunity is critical for limiting Plasmodium parasite infections and the severity of malaria. Naturally acquired immunity against malaria occurs inefficiently and protection is relatively ...short-lived. Here we review recent advances and explore emerging hypotheses regarding the molecular and cellular pathways that regulate Plasmodium parasite-specific B cell responses and durable anti-malarial humoral immunity.
IL-10 is a pleiotropic cytokine expressed during malaria, a disease characterized by short-lived, parasite-specific Ab responses. The role of IL-10 in regulating B cell responses during malaria is ...not known. In this study we report that IL-10 is essential for anti-Plasmodium humoral immunity. We identify that germinal center (GC) B cell reactions, isotype-switched Ab responses, parasite control, and host survival require B cell-intrinsic IL-10 signaling. IL-10 also indirectly supports humoral immunity by suppressing excessive IFN-γ, which induces T-bet expression in B cells. Genetic ablation of either IFN-γ signaling or T-bet expression in B cells substantially enhanced GC B cell responses and anti-Plasmodium Ab production. Together, our data show that B cell-intrinsic IL-10 enhances whereas B cell-intrinsic IFN-γ and T-bet suppress GC B cell responses and anti-Plasmodium humoral immunity. These data identify critical immunoregulatory circuits in B cells that may be targeted to promote long-lived humoral immunity and resistance to malaria.
T cell immunoglobulin mucin domain-1 (TIM-1) is a phosphatidylserine (PS) receptor, mediating filovirus entry into cells through interactions with PS on virions. TIM-1 expression has been implicated ...in Ebola virus (EBOV) pathogenesis; however, it remains unclear whether this is due to TIM-1 serving as a filovirus receptor in vivo or, as others have suggested, TIM-1 induces a cytokine storm elicited by T cell/virion interactions. Here, we use a BSL2 model virus that expresses EBOV glycoprotein to demonstrate the importance of TIM-1 as a virus receptor late during in vivo infection.
Infectious, GFP-expressing recombinant vesicular stomatitis virus encoding either full length EBOV glycoprotein (EBOV GP/rVSV) or mucin domain deleted EBOV glycoprotein (EBOV GPΔO/rVSV) was used to assess the role of TIM-1 during in vivo infection. GFP-expressing rVSV encoding its native glycoprotein G (G/rVSV) served as a control. TIM-1-sufficient or TIM-1-deficient BALB/c interferon α/β receptor-/- mice were challenged with these viruses. While G/rVSV caused profound morbidity and mortality in both mouse strains, TIM-1-deficient mice had significantly better survival than TIM-1-expressing mice following EBOV GP/rVSV or EBOV GPΔO/rVSV challenge. EBOV GP/rVSV or EBOV GPΔO/rVSV in spleen of infected animals was high and unaffected by expression of TIM-1. However, infectious virus in serum, liver, kidney and adrenal gland was reduced late in infection in the TIM-1-deficient mice, suggesting that virus entry via this receptor contributes to virus load. Consistent with higher virus loads, proinflammatory chemokines trended higher in organs from infected TIM-1-sufficient mice compared to the TIM-1-deficient mice, but proinflammatory cytokines were more modestly affected. To assess the role of T cells in EBOV GP/rVSV pathogenesis, T cells were depleted in TIM-1-sufficient and -deficient mice and the mice were challenged with virus. Depletion of T cells did not alter the pathogenic consequences of virus infection.
Our studies provide evidence that at late times during EBOV GP/rVSV infection, TIM-1 increased virus load and associated mortality, consistent with an important role of this receptor in virus entry. This work suggests that inhibitors which block TIM-1/virus interaction may serve as effective antivirals, reducing virus load at late times during EBOV infection.
In a recent publication, Ramalho et al. investigated monocyte-derived dendritic cell (MODC) mobilization in response to Plasmodium infection. The authors showed that elevated levels of itaconate in ...MODCs results in reduced CD8 T cell activation and that the absence of itaconate is associated with enhanced parasite control.
In a recent publication, Ramalho et al. investigated monocyte-derived dendritic cell (MODC) mobilization in response to Plasmodium infection. The authors showed that elevated levels of itaconate in MODCs results in reduced CD8 T cell activation and that the absence of itaconate is associated with enhanced parasite control.
Malaria, caused by the protozoan Plasmodium, is a devastating mosquito-borne disease with the potential to affect nearly half the world's population. Despite mounting substantial T and B cell ...responses, humans fail to efficiently control blood-stage malaria or develop sterilizing immunity to reinfections. Although forkhead box P3 (FOXP3)
CD4
regulatory T (T
) cells form a part of these responses, their influence remains disputed and their mode of action is unknown. Here we show that T
cells expand in both humans and mice in blood-stage malaria and interfere with conventional T helper cell responses and follicular T helper (T
)-B cell interactions in germinal centers. Mechanistically, T
cells function in a critical temporal window to impede protective immunity through cytotoxic-T-lymphocyte-associated protein-4 (CTLA-4). Targeting T
cells or CTLA-4 in this precise window accelerated parasite clearance and generated species-transcending immunity to blood-stage malaria in mice. Our study uncovers a critical mechanism of immunosuppression associated with blood-stage malaria that delays parasite clearance and prevents development of potent adaptive immunity to reinfection. These data also reveal a temporally discrete and potentially therapeutically amenable functional role for T
cells and CTLA-4 in limiting antimalarial immunity.
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