LFA-1 Mediates Cytotoxicity and Tissue Migration of Specific CD8+ T Cells after Heterologous Prime-Boost Vaccination against Trypanosoma cruzi Infection

Ferreira, Camila Pontes; Cariste, Leonardo Moro; Virgilio, Fernando dos Santos; Moraschi, Barbara Ferri; Monteiro, Caroline Brandão; Machado, Alexandre de Tarso; Gazzinelli, Ricardo T.; Bruna-Romero, Oscar; Ruiz, Pedro Luiz Menin; Ribeiro, Daniel Araki; Lannes-Vieira, Joseli; Lopes, Marcela F.; Rodrigues, Maurício M.; Vasconcelos, José Ronnie

doi:10.3389/fimmu.2017.01291

Cited by 16 publications

(12 citation statements)

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“…In the spleen of chronically infected mice, CCL3 deficiency partially impaired CD8 + T-cells effector function, reducing IFNγ production after stimulus with the ASP2 T. cruzi antigen, in compatibility with the reduced frequency of IFNγ + CD8 + T-cells. However, the ASP2-specific cytotoxic activity was increased ccl3 −/− mice, paralleling the accumulation of CD8 + T-cells in spleen, and may contribute to systemic parasite control in the chronic infection, as cytotoxic CD8 + T-cells are crucial for parasite control (6,43).…”

Section: Discussionmentioning

confidence: 98%

“…Reduced number of circulating leukocytes paralleled the accumulation of CD8 + T-cells in spleen of chronically infected ccl3 −/− mice. Moreover, the frequency of splenic CCR5 + LFA-1 + among CD8 + T-cells, a population that gain the blood, enter the heart tissue and play effector functions (6,15,43), was reduced in T. cruziinfected ccl3 −/− mice. These findings support that cell activation, trafficking and colonization of the heart tissue was disturbed in chronically infected CCL3-deficient mice.…”

Section: Discussionmentioning

confidence: 99%

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CCL3/Macrophage Inflammatory Protein-1α Is Dually Involved in Parasite Persistence and Induction of a TNF- and IFNγ-Enriched Inflammatory Milieu in Trypanosoma cruzi-Induced Chronic Cardiomyopathy

et al. 2020

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CCL3, a member of the CC-chemokine family, has been associated with macrophage recruitment to heart tissue and parasite control in the acute infection of mouse with Trypanosoma cruzi, the causative agent of Chagas disease. Here, we approached the participation of CCL3 in chronic chagasic cardiomyopathy (CCC), the main clinical form of Chagas disease. We induced CCC in C57BL/6 (ccl3 +/+) and CCL3-deficient (ccl3 −/−) mice by infection with the Colombian Type I strain. In ccl3 +/+ mice, high levels of CCL3 mRNA and protein were detected in the heart tissue during the acute and chronic infection. Survival was not affected by CCL3 deficiency. In comparison with ccl3 +/+ , chronically infected ccl3 −/− mice presented reduced cardiac parasitism and inflammation due to CD8 + cells and macrophages. Leukocytosis was decreased in infected ccl3 −/− mice, paralleling the accumulation of CD8 + T cells devoid of activated CCR5 + LFA-1 + cells in the spleen. Further, T. cruzi-infected ccl3 −/− mice presented reduced frequency of interferon-gamma (IFNγ) + cells and numbers of parasite-specific IFNγ-producing cells, while the T. cruzi antigen-specific cytotoxic activity was increased. Stimulation of CCL3-deficient macrophages with IFNγ improved parasite control, in a milieu with reduced nitric oxide (NO x) and tumor necrosis factor (TNF), but similar interleukin-10 (IL-10), concentrations. In comparison with chronically T. cruzi-infected ccl3 +/+ counterparts, ccl3 −/− mice did not show enlarged heart, loss of left ventricular ejection fraction, QTc prolongation and elevated CK-MB activity. Compared with ccl3 +/+ , infected ccl3 −/− mice showed reduced concentrations of TNF, while IL-10 levels were not affected, in the heart milieu. In spleen of ccl3 +/+ NI controls, most of the CD8 + T-cells Gibaldi et al. CCL3 in T. cruzi-Induced Chronic Cardiomyopathy expressing the CCL3 receptors CCR1 or CCR5 were IL-10 + , while in infected mice these cells were mainly TNF +. Lastly, selective blockage of CCR1/CCR5 (Met-RANTES therapy) in chronically infected ccl3 +/+ mice reversed pivotal electrical abnormalities (bradycardia, prolonged PR, and QTc interval), in correlation with reduced TNF and, mainly, CCL3 levels in the heart tissue. Therefore, in the chronic T. cruzi infection CCL3 takes part in parasite persistence and contributes to form a CD8 + T-cell and macrophage-enriched cardiac inflammation. Further, increased levels of CCL3 create a scenario with abundant IFNγ and TNF, associated with cardiomyocyte injury, heart dysfunction and QTc prolongation, biomarkers of severity of Chagas' heart disease.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

CCL3/Macrophage Inflammatory Protein-1α Is Dually Involved in Parasite Persistence and Induction of a TNF- and IFNγ-Enriched Inflammatory Milieu in Trypanosoma cruzi-Induced Chronic Cardiomyopathy

et al. 2020

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“…Notably, in a recent study, Smith et al reported their work on variants controlling susceptibility to M. tuberculosis in the Collaborative Cross and that the Itgal gene is involved in the extreme susceptibility of CC042 mice to M. tuberculosis (46). Studies utilizing anti-LFA-1 antibodies to neutralize ITGAL protein activity have shown that ITGAL function is necessary for the timely clearance of respiratory syncytial virus (RSV) and for the control of parasitemia during Trypanosoma cruzi infection (36,47). In contrast, two separate studies have reported that Itgal Ϫ/Ϫ mice display increased resistance to Listeria monocytogenes infection (34,48).…”

Section: Discussionmentioning

confidence: 99%

A Loss-of-Function Mutation in the Integrin Alpha L (Itgal) Gene Contributes to Susceptibility to Salmonella enterica Serovar Typhimurium Infection in Collaborative Cross Strain CC042

et al. 2019

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Salmonella is an intracellular bacterium found in the gastrointestinal tract of mammalian, avian, and reptilian hosts. Mouse models have been extensively used to model in vivo distinct aspects of human Salmonella infections and have led to the identification of several host susceptibility genes. We have investigated the susceptibility of Collaborative Cross strains to intravenous infection with Salmonella enterica serovar Typhimurium as a model of human systemic invasive infection. In this model, strain CC042/GeniUnc (CC042) mice displayed extreme susceptibility with very high bacterial loads and mortality. CC042 mice showed lower spleen weights and decreased splenocyte numbers before and after infection, affecting mostly CD8+ T cells, B cells, and all myeloid cell populations, compared with control C57BL/6J mice. CC042 mice also had lower thymus weights with a reduced total number of thymocytes and double-negative and double-positive (CD4+, CD8+) thymocytes compared to C57BL/6J mice. Analysis of bone marrow-resident hematopoietic progenitors showed a strong bias against lymphoid-primed multipotent progenitors. An F2 cross between CC042 and C57BL/6N mice identified two loci on chromosome 7 (Stsl6 and Stsl7) associated with differences in bacterial loads. In the Stsl7 region, CC042 carried a loss-of-function variant, unique to this strain, in the integrin alpha L (Itgal) gene, the causative role of which was confirmed by a quantitative complementation test. Notably, Itgal loss of function increased the susceptibility to S. Typhimurium in a (C57BL/6J × CC042)F1 mouse background but not in a C57BL/6J mouse inbred background. These results further emphasize the utility of the Collaborative Cross to identify new host genetic variants controlling susceptibility to infections and improve our understanding of the function of the Itgal gene.

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“…This phenotype is likely partly explained by the Itgal deletion we have reported here. Studies utilizinganti-LFA-1 antibodies to neutralize ITGAL protein activity have shown that ITGAL function is necessary for timely clearance of respiratory syncytial virus (RSV) and for control of parasitemia during Trypanosoma cruzi infection [33, 43]. In contrast, two separate studies have reported that Itgal -/- mice display increased resistance to Listeria monocytogenes infection [31, 44].…”

Section: Discussionmentioning

confidence: 99%

A loss-of-function mutation inItgalcontributes to the high susceptibility of Collaborative Cross strain CC042 toSalmonellainfections

Zhang

Teh

et al. 2019

Preprint

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25Salmonella are intracellular bacteria that are found in the gastrointestinal tract of mammalian, 26 avian, and reptilian hosts. They are one of the leading causes of foodborne infections and a major 27 threat for human populations worldwide. Mouse models have been extensively used to model 28 distinct aspects of the human Salmonella infections in vivo and have led to the identification of 29 several host susceptibility genes. We have investigated the susceptibility of Collaborative Cross 30 strains to intravenous infection with Salmonella Typhimurium as a model of human systemic 31 invasive infection. In this model, strain CC042 displayed extreme susceptibility with very high 32 bacterial loads and mortality. CC042 mice showed lower spleen weight and decreased splenocyte 33 numbers before and after infection, affecting mostly CD8 + T cells, B cells, and all myeloid 34 populations. Uninfected mice also had lower thymus weight with reduced total number of 35 thymocytes and double negative and (CD4 + , CD8 + ) double positive thymocytes. Analysis of 36 bone marrow resident hematopoietic progenitors showed a strong bias against lymphoid primed 37 multipotent progenitors, which are the precursors of T, B and NK cells. An F2 cross between 38 CC042 and C57BL/6N identified two significant QTLs on chromosome 7 (Stsl6 and Stsl7) with 39 WSB-derived susceptible alleles. A private variant in the integrin alpha L (Itgal) gene is carried 40 by CC042 in the Stsl7 QTL region. A quantitative complementation test confirmed the impact of 41 Itgal loss of function in a (C57BL/6JxCC042)F1 background, but not in a C57BL/6J inbred 42 background. These results further emphasize the utility of the Collaborative Cross to identify 43 new host genetic variants controlling susceptibility to infections and improve our understanding 44 of the function of the Itgal gene. 45 46 3 47 Author summary 48 Salmonella are one of the leading causes of foodborne infections and a major threat for human 49 populations worldwide. Not all humans are equally susceptible to Salmonella infection. Some 50 individuals will develop minor symptoms and recover while others develop severe illness and 51 might die. Mouse models are used to study distinct aspects of human Salmonella infection in 52vivo. We used a new genetically diverse mouse population to investigate host susceptibility 53 differences to Salmonella infection. We identified one mouse strain with an extreme 54 susceptibility to infection characterized by very high bacterial loads and mortality. Mice of this 55 strain had small thymus and spleen, two organs which are very important for producing a fully 56 mature immune system. We showed that the strain's immune response is impaired and that its 57 extreme susceptibility to Salmonella infection is due to multiple genes defects. We identified a 58 loss-of-function mutation in the Itgal gene (Integrin Subunit Alpha L) that plays a central role in 59 the immune response to infection. This gene explains part of the susceptibility and other gene(s) 60 in...

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LFA-1 Mediates Cytotoxicity and Tissue Migration of Specific CD8+ T Cells after Heterologous Prime-Boost Vaccination against Trypanosoma cruzi Infection

Cited by 16 publications

References 47 publications

CCL3/Macrophage Inflammatory Protein-1α Is Dually Involved in Parasite Persistence and Induction of a TNF- and IFNγ-Enriched Inflammatory Milieu in Trypanosoma cruzi-Induced Chronic Cardiomyopathy

CCL3/Macrophage Inflammatory Protein-1α Is Dually Involved in Parasite Persistence and Induction of a TNF- and IFNγ-Enriched Inflammatory Milieu in Trypanosoma cruzi-Induced Chronic Cardiomyopathy

A Loss-of-Function Mutation in the Integrin Alpha L (Itgal) Gene Contributes to Susceptibility to Salmonella enterica Serovar Typhimurium Infection in Collaborative Cross Strain CC042

A loss-of-function mutation inItgalcontributes to the high susceptibility of Collaborative Cross strain CC042 toSalmonellainfections

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