scholarly journals Vaccinated C57BL/6 Mice Develop Protective and Memory T Cell Responses to Coccidioides posadasii Infection in the Absence of Interleukin-10

2013 ◽  
Vol 82 (2) ◽  
pp. 903-913 ◽  
Author(s):  
Chiung-Yu Hung ◽  
Natalia Castro-Lopez ◽  
Garry T. Cole
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Interleukin 10 ◽  
Effector Memory ◽  
Wild Type ◽  
Coccidioides Posadasii ◽  
Content Type ◽  
Cell Immunity ◽  
Ifn Γ

ABSTRACTHigh concentrations of lung tissue-associated interleukin-10 (IL-10), an anti-inflammatory and immunosuppressive cytokine, correlate with susceptibility of mice toCoccidioidesspp. infection. In this study, we found that macrophages, dendritic cells, neutrophils, and both CD8+and CD4+T cells recruited toCoccidioides posadasii-infected lungs of nonvaccinated and vaccinated mice contributed to the production of IL-10. The major IL-10-producing leukocytes were CD8+T cells, neutrophils, and macrophages in lungs of nonvaccinated mice, while both Foxp3+and Foxp3−subsets of IL-10+CD4+T cells were significantly elevated in vaccinated mice. Profiles of the recruited leukocytes in lungs revealed that only CD4+T cells were significantly increased inIL-10−/−knockout mice compared to their wild-type counterparts. Furthermore,ex vivorecall assays showed that CD4+T cells isolated from vaccinatedIL-10−/−mice compared to vaccinated wild-type mice produced significantly higher amounts of IL-2, gamma interferon (IFN-γ), IL-4, IL-6, and IL-17A in the presence of a coccidioidal antigen, indicating that IL-10 suppresses Th1, Th2, and Th17 immunity toCoccidioidesinfection. Analysis of absolute numbers of CD44+CD62L−CD4+T effector memory T cells (TEM) and IFN-γ- and IL-17A-producing CD4+T cells in the lungs ofCoccidioides-infected mice correlated with better fungal clearance in nonvaccinatedIL-10−/−mice than in nonvaccinated wild-type mice. Our results suggest that IL-10 suppresses CD4+T-cell immunity in nonvaccinated mice duringCoccidioidesinfection but does not impede the development of a memory response nor exacerbate immunopathology of vaccinated mice over at least a 4-month period after the last immunization.

scholarly journals Protective Immunity against Experimental Pulmonary Cryptococcosis in T Cell-Depleted Mice

2011 ◽  
Vol 18 (5) ◽  
pp. 717-723 ◽  
Author(s):  
Karen L. Wozniak ◽  
Mattie L. Young ◽  
Floyd L. Wormley
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protective Immunity ◽  
Effector Memory ◽  
Cell Phenotype ◽  
Cell Mediated Immunity ◽  
Wild Type ◽  
Pulmonary Cryptococcosis ◽  
Content Type ◽  
Immunocompetent Mice

ABSTRACTIndividuals with defects in T cell-mediated immunity (CMI) are highly susceptible to infection withCryptococcus neoformans. The purpose of these studies was to determine if protection against experimental pulmonary cryptococcosis can be generated in T cell-deficient hosts. BALB/c mice were depleted of CD4+and/or CD8+T cells or given an isotype control antibody prior to vaccination with aC. neoformansstrain, designated H99γ, previously shown to induce protection againstC. neoformansinfection in immunocompetent mice. Mice depleted of CD4+or CD8+T cells, but not both subsets, survived an acute pulmonary infection withC. neoformansstrain H99γ and a subsequent second challenge with wild-typeC. neoformansstrain H99. We observed a significant increase in the percentage of CD4+and CD8+T cells expressing the activation marker CD69 in the lungs of mice immunized withC. neoformansstrain H99γ prior to a secondary challenge with wild-type cryptococci. CD4+T cells within the lungs of immunized mice also appeared to acquire a predominantly activated effector memory cell phenotype (CD69+CD44+CCR7−CD45RB−CD62L−) following a second pulmonary challenge with wild-typeC. neoformans, compared to CD4+T cells from naïve mice. Lastly, immunization of immunocompetent mice withC. neoformansstrain H99γ prior to depletion of CD4+and/or CD8+T cells resulted in significant protection against a second challenge with wild-typeC. neoformans. Our studies demonstrate that protective immunity against pulmonary cryptococcosis can be generated in immunosuppressed hosts, thus supporting the development of cryptococcal vaccines.

scholarly journals The immunomodulatory drugs lenalidomide and pomalidomide enhance the potency of AMG 701 in multiple myeloma preclinical models

2020 ◽  
Vol 4 (17) ◽  
pp. 4195-4207
Author(s):  
Shih-Feng Cho ◽  
Liang Lin ◽  
Lijie Xing ◽  
Yuyin Li ◽  
Kenneth Wen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Interleukin 10 ◽  
Cytolytic Activity ◽  
Effector Memory ◽  
Immunomodulatory Drugs ◽  
T Effector Cells ◽  
The Impact

Abstract We investigated here the novel immunomodulation and anti–multiple myeloma (MM) function of T cells engaged by the bispecific T-cell engager molecule AMG 701, and further examined the impact of AMG 701 in combination with immunomodulatory drugs (IMiDs; lenalidomide and pomalidomide). AMG 701 potently induced T-cell–dependent cellular cytotoxicity (TDCC) against MM cells expressing B-cell maturation antigen, including autologous cells from patients with relapsed and refractory MM (RRMM) (half maximal effective concentration, <46.6 pM). Besides inducing T-cell proliferation and cytolytic activity, AMG 701 also promoted differentiation of patient T cells to central memory, effector memory, and stem cell–like memory (scm) phenotypes, more so in CD8 vs CD4 T subsets, resulting in increased CD8/CD4 ratios in 7-day ex vivo cocultures. IMiDs and AMG 701 synergistically induced TDCC against MM cell lines and autologous RRMM patient cells, even in the presence of immunosuppressive bone marrow stromal cells or osteoclasts. IMiDs further upregulated AMG 701–induced patient T-cell differentiation toward memory phenotypes, associated with increased CD8/CD4 ratios, increased Tscm, and decreased interleukin 10–positive T and T regulatory cells (CD25highFOXP3high), which may downregulate T effector cells. Importantly, the combination of AMG 701 with lenalidomide induced sustained inhibition of MM cell growth in SCID mice reconstituted with human T cells; tumor regrowth was eventually observed in cohorts treated with either agent alone (P < .001). These results strongly support AMG 701 clinical studies as monotherapy in patients with RRMM (NCT03287908) and the combination with IMiDs to improve patient outcomes in MM.

scholarly journals Early Induction of Interleukin-10 Limits Antigen-Specific CD4+T Cell Expansion, Function, and Secondary Recall Responses during Persistent Phagosomal Infection

2014 ◽  
Vol 82 (10) ◽  
pp. 4092-4103 ◽  
Author(s):  
Abinav Kumar Singh ◽  
Nagaraja R. Thirumalapura
Keyword(s):  
T Cells ◽  
T Cell ◽  
Functional Status ◽  
Persistent Infection ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Interleukin 10 ◽  
Host Cells ◽  
Content Type ◽  
Ifn Γ

ABSTRACTDiverse pathogens have evolved to survive and replicate in the endosomes or phagosomes of the host cells and establish persistent infection. Ehrlichiae are Gram-negative, intracellular bacteria that are transmitted by ticks. Ehrlichiae reside in the endosomes of the host phagocytic or endothelial cells and establish persistent infection in their vertebrate reservoir hosts. CD4+T cells play a critical role in protection against phagosomal infections. In the present study, we investigated the expansion, maintenance, and functional status of antigen-specific CD4+T cells during persistentEhrlichia murisinfection in wild-type and interleukin-10 (IL-10)-deficient mice. Our study indicated that early induction of IL-10 led to reduced inflammatory responses and impaired bacterial clearance during persistentEhrlichiainfection. Notably, we demonstrated that the functional production of gamma interferon (IFN-γ) by antigen-specific CD4+T cells maintained during a persistent phagosomal infection progressively deteriorates. The functional loss of IFN-γ production by antigen-specific CD4+T cells was reversed in the absence of IL-10. Furthermore, we demonstrated that transient blockade of IL-10 receptor during the T cell priming phase early in infection was sufficient to enhance the magnitude and the functional capacity of antigen-specific effector and memory CD4+T cells, which translated into an enhanced recall response. Our findings provide new insights into the functional status of antigen-specific CD4+T cells maintained during persistent phagosomal infection. The study supports the concept that a better understanding of the factors that influence the priming and differentiation of CD4+T cells may provide a basis to induce a protective immune response against persistent infections.

scholarly journals Tpl2 Promotes Innate Cell Recruitment and Effector T Cell Differentiation To Limit Citrobacter rodentium Burden and Dissemination

2017 ◽  
Vol 85 (10) ◽  
Author(s):  
Nicole V. Acuff ◽  
Xin Li ◽  
Krishna Latha ◽  
Tamas Nagy ◽  
Wendy T. Watford
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Immune Cell ◽  
Cd4 T Cell ◽  
Citrobacter Rodentium ◽  
Wild Type ◽  
Content Type ◽  
Cell Recruitment ◽  
Ifn Γ

ABSTRACT Tumor progression locus 2 (Tpl2) is a serine-threonine kinase that regulates Th1 differentiation, secretion of the inflammatory cytokine gamma interferon (IFN-γ), and host defense against the intracellular pathogens Toxoplasma gondii, Listeria monocytogenes, and Mycobacterium tuberculosis. However, relatively little is known about the contribution of Tpl2 to Th17 differentiation and immune cell function during infection with an extracellular pathogen. The goal of this study was to determine whether Tpl2 influences the immune response generated to the extracellular bacterium Citrobacter rodentium, which induces a mixed Th1 and Th17 response. During peak infection with C. rodentium, Tpl2 −/− mice experienced greater bacterial burdens with evidence of dissemination to the liver and spleen but ultimately cleared the bacteria within 3 weeks postinfection, similar to the findings for wild-type mice. Tpl2 −/− mice also recruited fewer neutrophils and monocytes to the colon during peak infection, which correlated with increased bacterial burdens. In mixed bone marrow chimeras, Tpl2 was shown to play a T cell-intrinsic role in promoting both IFN-γ and interleukin-17A production during infection with C. rodentium. However, upon CD4 T cell transfer into Rag −/− mice, Tpl2 −/− CD4 T cells were as protective as wild-type CD4 T cells against the dissemination of bacteria and mortality. These data indicate that the enhanced bacterial burdens in Tpl2 −/− mice are not caused primarily by impairments in CD4 T cell function but result from defects in innate immune cell recruitment and function.

scholarly journals T Cell-Independent Gamma Interferon and B Cells Cooperate To Prevent Mortality Associated with DisseminatedChlamydia muridarumGenital Tract Infection

2018 ◽  
Vol 86 (7) ◽  
pp. e00143-18 ◽  
Author(s):  
Taylor B. Poston ◽  
Catherine M. O'Connell ◽  
Jenna Girardi ◽  
Jeanne E. Sullivan ◽  
Uma M. Nagarajan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Tract Infection ◽  
B Cell ◽  
Gamma Interferon ◽  
Wild Type ◽  
Content Type ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACTCD4 T cells and antibody are required for optimal acquired immunity toChlamydia muridarumgenital tract infection, and T cell-mediated gamma interferon (IFN-γ) production is necessary to clear infection in the absence of humoral immunity. However, the role of T cell-independent immune responses during primary infection remains unclear. We investigated this question by inoculating wild-type and immune-deficient mice withC. muridarumCM001, a clonal isolate capable of enhanced extragenital replication. Genital inoculation of wild-type mice resulted in transient dissemination to the lungs and spleen that then was rapidly cleared from these organs. However, CM001 genital infection proved lethal forSTAT1−/−andIFNG−/−mice, in which IFN-γ signaling was absent, and forRag1−/−mice, which lacked T and B cells and in which innate IFN-γ signaling was retained. In contrast, B cell-deficient muMT mice, which can generate a Th1 response, and T cell-deficient mice with intact B cell and innate IFN-γ signaling survived. These data collectively indicate that IFN-γ prevents lethal CM001 dissemination in the absence of T cells and suggests a B cell corequirement. Adoptive transfer of convalescent-phase immune serum but not naive IgM toRag1−/−mice infected with CM001 significantly increased the survival time, while transfer of naive B cells completely rescuedRag1−/−mice from CM001 lethality. Protection was associated with a significant reduction in the lung chlamydial burden of genitally infected mice. These data reveal an important cooperation between T cell-independent B cell responses and innate IFN-γ in chlamydial host defense and suggest that interactions between T cell-independent antibody and IFN-γ are essential for limiting extragenital dissemination.

scholarly journals Off-the-Shelf Partial HLA Matching SARS-CoV-2 Antigen Specific T Cell Therapy: A New Possibility for COVID-19 Treatment

2021 ◽  
Vol 12 ◽  
Author(s):  
Nayoun Kim ◽  
Jong-Min Lee ◽  
Eun-Jee Oh ◽  
Dong Wook Jekarl ◽  
Dong-Gun Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Third Party ◽  
Effector Memory ◽  
Antigen Specificity ◽  
Hla Matching ◽  
T Cell Therapy ◽  
Cell Immunity

BackgroundImmunological characteristics of COVID-19 show pathological hyperinflammation associated with lymphopenia and dysfunctional T cell responses. These features provide a rationale for restoring functional T cell immunity in COVID-19 patients by adoptive transfer of SARS-CoV-2 specific T cells.MethodsTo generate SARS-CoV-2 specific T cells, we isolated peripheral blood mononuclear cells from 7 COVID-19 recovered and 13 unexposed donors. Consequently, we stimulated cells with SARS-CoV-2 peptide mixtures covering spike, membrane and nucleocapsid proteins. Then, we culture expanded cells with IL-2 for 21 days. We assessed immunophenotypes, cytokine profiles, antigen specificity of the final cell products.ResultsOur results show that SARS-CoV-2 specific T cells could be expanded in both COVID-19 recovered and unexposed groups. Immunophenotypes were similar in both groups showing CD4+ T cell dominance, but CD8+ and CD3+CD56+ T cells were also present. Antigen specificity was determined by ELISPOT, intracellular cytokine assay, and cytotoxicity assays. One out of 14 individuals who were previously unexposed to SARS-CoV-2 failed to show antigen specificity. Moreover, ex-vivo expanded SARS-CoV-2 specific T cells mainly consisted of central and effector memory subsets with reduced alloreactivity against HLA-unmatched cells suggesting the possibility for the development of third-party partial HLA-matching products.DiscussionIn conclusion, our findings show that SARS-CoV-2 specific T cell can be readily expanded from both COVID-19 and unexposed individuals and can therefore be manufactured as a biopharmaceutical product to treat severe COVID-19 patients.One Sentence SummaryEx-vivo expanded SARS-CoV-2 antigen specific T cells developed as third-party partial HLA-matching products may be a promising approach for treating severe COVID-19 patients that do not respond to previous treatment options.

scholarly journals Distinct Contributions of CD4+and CD8+T Cells to Pathogenesis of Trypanosoma brucei Infection in the Context of Gamma Interferon and Interleukin-10

2015 ◽  
Vol 83 (7) ◽  
pp. 2785-2795 ◽  
Author(s):  
Gongguan Liu ◽  
Donglei Sun ◽  
Hui Wu ◽  
Mingshun Zhang ◽  
Haixia Huan ◽  
...  
Keyword(s):  
T Cells ◽  
Trypanosoma Brucei ◽  
Interleukin 10 ◽  
Gamma Interferon ◽  
Wild Type ◽  
Survival Times ◽  
Independent Manner ◽  
Content Type ◽  
Ifn Γ ◽  
Excessive Secretion

Although gamma interferon (IFN-γ) and interleukin-10 (IL-10) have been shown to be critically involved in the pathogenesis of African trypanosomiasis, the contributions to this disease of CD4+and CD8+T cells, the major potential producers of the two cytokines, are incompletely understood. Here we show that, in contrast to previous findings, IFN-γ was produced by CD4+, but not CD8+, T cells in mice infected withTrypanosoma brucei. Without any impairment in the secretion of IFN-γ, infected CD8−/−mice survived significantly longer than infected wild-type mice, suggesting that CD8+T cells mediated mortality in an IFN-γ-independent manner. The increased survival of infected CD8−/−mice was significantly reduced in the absence of IL-10 signaling. Interestingly, IL-10 was also secreted mainly by CD4+T cells. Strikingly, depletion of CD4+T cells abrogated the prolonged survival of infected CD8−/−mice, demonstrating that CD4+T cells mediated protection. Infected wild-type mice and CD8−/−mice depleted of CD4+T cells had equal survival times, suggesting that the protection mediated by CD4+T cells was counteracted by the detrimental effects of CD8+T cells in infected wild-type mice. Interestingly, CD4+T cells also mediated the mortality of infected mice in the absence of IL-10 signaling, probably via excessive secretion of IFN-γ. Finally, CD4+, but not CD8+, T cells were critically involved in the synthesis of IgG antibodies duringT. bruceiinfections. Collectively, these results highlight distinct roles of CD4+and CD8+T cells in the context of IFN-γ and IL-10 duringT. bruceiinfections.

scholarly journals Differentiation of Antigen-Specific T Cells with Limited Functional Capacity during Mycobacterium tuberculosis Infection

2013 ◽  
Vol 82 (1) ◽  
pp. 132-139 ◽  
Author(s):  
Yun Hee Jeong ◽  
Bo-Young Jeon ◽  
Sun-Hwa Gu ◽  
Sang-Nae Cho ◽  
Sung Jae Shin ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Memory T Cells ◽  
Interleukin 2 ◽  
Effector Memory ◽  
Memory Cells ◽  
Content Type ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACTDespite the generation ofMycobacterium tuberculosis-specific T cell immune responses during the course of infection, only 5 to 10% of exposed individuals develop active disease, while others develop a latent infection. This phenomenon suggests defectiveM. tuberculosis-specific immunity, which necessitates more careful characterization ofM. tuberculosis-specific T cell responses. Here, we longitudinally analyzed the phenotypes and functions ofM. tuberculosis-specific T cells. In contrast to the functional exhaustion of T cells observed after chronic infection,M. tuberculosis-specific CD8+T cells differentiated into either effector (CD127loCD62Llo) or effector memory (CD127hiCD62Llo) cells, but not central memory cells (CD127hiCD62Lhi), with low programmed death 1 (PD-1) expression, even in the presence of high levels of bacteria. Additionally,M. tuberculosis-specific CD8+and CD4+T cells produced substantial levels of tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ), but not interleukin 2 (IL-2), uponin vitrorestimulation. AmongM. tuberculosis-specific CD8+T cells, CD127hieffector memory cells displayed slower ongoing turnover but greater survival potential. In addition, these cells produced more IFN-γ and TNF-α and displayed lytic activity upon antigen stimulation. However, the effector function ofM. tuberculosis-specific CD8+CD127hieffector memory T cells was inferior to that of canonical CD8+CD127himemory T cells generated after acute lymphocytic choriomeningitis virus infection. Collectively, our data demonstrate thatM. tuberculosis-specific T cells can differentiate into memory T cells during the course ofM. tuberculosisinfection independent of the bacterial burden but with limited functionality. These results provide a framework for further understanding the mechanisms ofM. tuberculosisinfection that can be used to develop more effective vaccines.

TGF-Beta Signaling Favors Central Memory Phenotype Expression By Ex-Vivo Stimulated Human T Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3841-3841 ◽  
Author(s):  
Amina Dahmani ◽  
Cédric Carli ◽  
Julie Taillefer ◽  
Mathieu Goupil ◽  
Myriam Khalili ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adoptive Immunotherapy ◽  
Cell Biology ◽  
Ex Vivo ◽  
Central Memory ◽  
Effector Memory ◽  
Therapeutic Effects ◽  
Ifn Γ ◽  
Phenotype Expression

Abstract Adoptive immunotherapy using ex vivo differentiated and expanded T cell lines can be remarkably efficient to treat cancer and infections. Unfortunately, the process of ex vivo T cell stimulation can lead to terminal effector differentiation and functional exhaustion thereby limiting the persistence and therapeutic effects of these T cells after transfer. Accumulating evidence suggests that, owing to their proliferative capacity, self-renewal ability and long term persistence in vivo, T cells bearing a central memory (CD45RO+/CD62L+ - Tcm) instead of an effector memory (CD45RO+/CD62L- - Tem) phenotype before adoptive transfer can mediate more significant therapeutic activity. Transforming-growth factor-beta (TGF-β) is a pleiotropic cytokine that influences several aspects of T-cell biology and that is best known for its growth suppression and immunosuppressive activity. We show that TGF-β signaling can have a profound impact on the number of CD4 and CD8 T cells expressing the Tcm and Tem phenotype after anti-CD3e and anti-CD28 stimulation without altering the number of cells recovered at the end of the culture and without inducing regulatory T cells. By enhancing the percentage of the lymph-node homing receptors, L-selectin (CD62L) and CC-chemokine receptor 7 (CCR7) expressing cells, exogenous TGF-β, added to the culture medium to a concentration of 5 ng/ml, favors Tcm over Tem cell accumulation at 7 days (CD4+: 55.80 vs 35.51% (P= 0.0074); CD8+: 56.9 vs 40.3% (P= 0.0063)). Reciprocally, the inhibition of TGF-β signaling with a TGF-β receptor kinase inhibitor (GW788388) accentuated Tem phenotype acquisition. Importantly, these effects of TGF-β on Tcm marker expression were maintained in the presence of exogenous cytokines commonly used in ex-vivo cultures for adoptive immunotherapy (IL-2, IL-7 and IL-15). The manipulation of TGF-β signaling did not increase the expression of exhaustion markers (KRLG-1, CD57) but exogenous TGF-β decreased interferon-gamma (IFN-γ) expression. No effect was noted on TNF-α and IL-2 expression as well as on the percentage of polyfunctional cells generated. We also found that modulating TGF-β signaling during the course of clinically relevant cultures capable of expanding T-cells specific for Epstein-Barr virus LMP2 protein antigens, in the presence of IL-7 and IL-15, could increase the number of CD4 Tcm cells, even 2 weeks after the withdrawal of TGF-β from the culture (38.24 vs 27.82, N=3) without compromising antigen-specific IFN-γ release. In conclusion, the modulation of TGF-β signaling can significantly alter Tcm and Tem phenotype acquisition and may therefore be used to optimize Tcm phenotype expression by ex-vivo pathogen/antigen-specific T cells expanded for adoptive immunotherapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Host Resistance to Plasmodium-Induced Acute Immune Pathology Is Regulated by Interleukin-10 Receptor Signaling

2017 ◽  
Vol 85 (6) ◽  
Author(s):  
Carla Claser ◽  
J. Brian De Souza ◽  
Samuel G. Thorburn ◽  
Georges Emile Grau ◽  
Eleanor M. Riley ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Host Resistance ◽  
Interleukin 10 ◽  
Experimental Cerebral Malaria ◽  
Content Type ◽  
Ifn Γ ◽  
Immune Pathology

ABSTRACT The resolution of malaria infection is dependent on a balance between proinflammatory and regulatory immune responses. While early effector T cell responses are required for limiting parasitemia, these responses need to be switched off by regulatory mechanisms in a timely manner to avoid immune-mediated tissue damage. Interleukin-10 receptor (IL-10R) signaling is considered to be a vital component of regulatory responses, although its role in host resistance to severe immune pathology during acute malaria infections is not fully understood. In this study, we have determined the contribution of IL-10R signaling to the regulation of immune responses during Plasmodium berghei ANKA-induced experimental cerebral malaria (ECM). We show that antibody-mediated blockade of the IL-10R during P. berghei ANKA infection in ECM-resistant BALB/c mice leads to amplified T cell activation, higher serum gamma interferon (IFN-γ) concentrations, enhanced intravascular accumulation of both parasitized red blood cells and CD8+ T cells to the brain, and an increased incidence of ECM. Importantly, the pathogenic effects of IL-10R blockade during P. berghei ANKA infection were reversible by depletion of T cells and neutralization of IFN-γ. Our findings underscore the importance of IL-10R signaling in preventing T-cell- and cytokine-mediated pathology during potentially lethal malaria infections.

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