Self and parasite-derived peptides selected upon DERAA-bearing HLA-DRB1 alleles activate CD4+ T cells from Chagas cardiomyopathy patients and are associated with ventricular dysfunction
IntroductionHuman infection with the protozoan Trypanosoma cruzi causes Chagas disease, which may lead to a deadly dilated cardiomyopathy resulting from T-cell-mediated inflammation. We found that specific HLA-DRB1 alleles (*0103, *0402, *1301, and *1302) that display the DERAA motif are linked to t...
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2025-05-01
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| author | Thaiany G. Souza-Silva Eula G. A. Neves Andrea Teixeira-Carvalho Amanda Braga Figueiredo Katia Luciano Pereira Morais Juliana Apostólico Hélcio Rodrigues Jorge Kalil Maria Aparecida Juliano Luiz Juliano Silvana Silva Araújo Alexandre Negrão Pantaleao Antônio Mutarelli Maria Carmo Pereira Nunes Kenneth J. Gollob Kenneth J. Gollob Walderez O. Dutra Walderez O. Dutra |
| author_facet | Thaiany G. Souza-Silva Eula G. A. Neves Andrea Teixeira-Carvalho Amanda Braga Figueiredo Katia Luciano Pereira Morais Juliana Apostólico Hélcio Rodrigues Jorge Kalil Maria Aparecida Juliano Luiz Juliano Silvana Silva Araújo Alexandre Negrão Pantaleao Antônio Mutarelli Maria Carmo Pereira Nunes Kenneth J. Gollob Kenneth J. Gollob Walderez O. Dutra Walderez O. Dutra |
| author_sort | Thaiany G. Souza-Silva |
| collection | DOAJ |
| description | IntroductionHuman infection with the protozoan Trypanosoma cruzi causes Chagas disease, which may lead to a deadly dilated cardiomyopathy resulting from T-cell-mediated inflammation. We found that specific HLA-DRB1 alleles (*0103, *0402, *1301, and *1302) that display the DERAA motif are linked to this severe clinical manifestation of Chagas disease.MethodsWe employed computational analysis, in vitro functional assays, and single-cell RNA sequencing to determine the response of CD4+ T cells from indeterminate (IND) and cardiac (CCC) Chagas patients to peptides selected on DERAA-bearing alleles.ResultsWe observed that these alleles display binding affinity towards host-derived peptides with sequence similarity to parasite-derived proteins. These peptides can activate and induce proliferation of CD4+ T-cells from CCC, but not IND. Importantly, the magnitude of this response correlated with the severity of ventricular dysfunction and increased production of soluble factors associated with myocardial fibrosis. Analysis of differentially expressed genes (DEGs) in activated CD4+ T-cells from individuals with the DERAA-DRB1 alleles demonstrated a high expression of cytotoxic, chemotactic and proapoptotic genes, linking these cells with pathogenic functions. Finally, we observed the upregulation of genes that code for the host proteins that contain the potentially pathogenic peptides in the cardiac tissue of CCC, suggesting their involvement in cardiomyopathy.DiscussionOur findings highlight the ability of CD4+ T-cells from CCC patients to recognize and react to foreign and self-peptides, thereby emphasizing the importance of HLA-DRB1 alleles in the presentation of potentially pathogenic antigens and in the amplification of CCC pathology. |
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| issn | 1664-3224 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-d1c2a0df2b8a41858b8ebdad95c33c572025-08-20T01:48:57ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-05-011610.3389/fimmu.2025.15271151527115Self and parasite-derived peptides selected upon DERAA-bearing HLA-DRB1 alleles activate CD4+ T cells from Chagas cardiomyopathy patients and are associated with ventricular dysfunctionThaiany G. Souza-Silva0Eula G. A. Neves1Andrea Teixeira-Carvalho2Amanda Braga Figueiredo3Katia Luciano Pereira Morais4Juliana Apostólico5Hélcio Rodrigues6Jorge Kalil7Maria Aparecida Juliano8Luiz Juliano9Silvana Silva Araújo10Alexandre Negrão Pantaleao11Antônio Mutarelli12Maria Carmo Pereira Nunes13Kenneth J. Gollob14Kenneth J. Gollob15Walderez O. Dutra16Walderez O. Dutra17Laboratório Biologia das Interações Celulares, Depto. Morfologia, Instituto de Ciências Biológicas, Belo Horizonte, MG, BrazilLaboratório Biologia das Interações Celulares, Depto. Morfologia, Instituto de Ciências Biológicas, Belo Horizonte, MG, BrazilInstituto René Rachou, Fundação Oswaldo Cruz (FIOCRUZ), Belo Horizonte, MG, BrazilCenter for Research in Immuno-Oncology (CRIO), Hospital Israelita Albert Einstein, São Paulo, SP, BrazilCenter for Research in Immuno-Oncology (CRIO), Hospital Israelita Albert Einstein, São Paulo, SP, BrazilCenter for Research in Immuno-Oncology (CRIO), Hospital Israelita Albert Einstein, São Paulo, SP, BrazilLaboratory of Immunology, Heart Institute, Instituto do Coração (InCor), School of Medicine, University of São Paulo, São Paulo, SP, BrazilLaboratory of Immunology, Heart Institute, Instituto do Coração (InCor), School of Medicine, University of São Paulo, São Paulo, SP, BrazilDepartamento de Biofísica, Escola Paulista de Medicina, UNIFESP, São Paulo, SP, BrazilDepartamento de Biofísica, Escola Paulista de Medicina, UNIFESP, São Paulo, SP, BrazilDepto. Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, BrazilDepto. Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, BrazilDepto. Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, BrazilDepto. Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, BrazilCenter for Research in Immuno-Oncology (CRIO), Hospital Israelita Albert Einstein, São Paulo, SP, BrazilInstituto Nacional de Ciência e Tecnologia em Doenças Tropicais, Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais (INCT-DT), Belo Horizonte, BrazilLaboratório Biologia das Interações Celulares, Depto. Morfologia, Instituto de Ciências Biológicas, Belo Horizonte, MG, BrazilInstituto Nacional de Ciência e Tecnologia em Doenças Tropicais, Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais (INCT-DT), Belo Horizonte, BrazilIntroductionHuman infection with the protozoan Trypanosoma cruzi causes Chagas disease, which may lead to a deadly dilated cardiomyopathy resulting from T-cell-mediated inflammation. We found that specific HLA-DRB1 alleles (*0103, *0402, *1301, and *1302) that display the DERAA motif are linked to this severe clinical manifestation of Chagas disease.MethodsWe employed computational analysis, in vitro functional assays, and single-cell RNA sequencing to determine the response of CD4+ T cells from indeterminate (IND) and cardiac (CCC) Chagas patients to peptides selected on DERAA-bearing alleles.ResultsWe observed that these alleles display binding affinity towards host-derived peptides with sequence similarity to parasite-derived proteins. These peptides can activate and induce proliferation of CD4+ T-cells from CCC, but not IND. Importantly, the magnitude of this response correlated with the severity of ventricular dysfunction and increased production of soluble factors associated with myocardial fibrosis. Analysis of differentially expressed genes (DEGs) in activated CD4+ T-cells from individuals with the DERAA-DRB1 alleles demonstrated a high expression of cytotoxic, chemotactic and proapoptotic genes, linking these cells with pathogenic functions. Finally, we observed the upregulation of genes that code for the host proteins that contain the potentially pathogenic peptides in the cardiac tissue of CCC, suggesting their involvement in cardiomyopathy.DiscussionOur findings highlight the ability of CD4+ T-cells from CCC patients to recognize and react to foreign and self-peptides, thereby emphasizing the importance of HLA-DRB1 alleles in the presentation of potentially pathogenic antigens and in the amplification of CCC pathology.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1527115/fullChagas diseaseHLA-DRB1cardiomyopathycross-reactivityT-cells |
| spellingShingle | Thaiany G. Souza-Silva Eula G. A. Neves Andrea Teixeira-Carvalho Amanda Braga Figueiredo Katia Luciano Pereira Morais Juliana Apostólico Hélcio Rodrigues Jorge Kalil Maria Aparecida Juliano Luiz Juliano Silvana Silva Araújo Alexandre Negrão Pantaleao Antônio Mutarelli Maria Carmo Pereira Nunes Kenneth J. Gollob Kenneth J. Gollob Walderez O. Dutra Walderez O. Dutra Self and parasite-derived peptides selected upon DERAA-bearing HLA-DRB1 alleles activate CD4+ T cells from Chagas cardiomyopathy patients and are associated with ventricular dysfunction Frontiers in Immunology Chagas disease HLA-DRB1 cardiomyopathy cross-reactivity T-cells |
| title | Self and parasite-derived peptides selected upon DERAA-bearing HLA-DRB1 alleles activate CD4+ T cells from Chagas cardiomyopathy patients and are associated with ventricular dysfunction |
| title_full | Self and parasite-derived peptides selected upon DERAA-bearing HLA-DRB1 alleles activate CD4+ T cells from Chagas cardiomyopathy patients and are associated with ventricular dysfunction |
| title_fullStr | Self and parasite-derived peptides selected upon DERAA-bearing HLA-DRB1 alleles activate CD4+ T cells from Chagas cardiomyopathy patients and are associated with ventricular dysfunction |
| title_full_unstemmed | Self and parasite-derived peptides selected upon DERAA-bearing HLA-DRB1 alleles activate CD4+ T cells from Chagas cardiomyopathy patients and are associated with ventricular dysfunction |
| title_short | Self and parasite-derived peptides selected upon DERAA-bearing HLA-DRB1 alleles activate CD4+ T cells from Chagas cardiomyopathy patients and are associated with ventricular dysfunction |
| title_sort | self and parasite derived peptides selected upon deraa bearing hla drb1 alleles activate cd4 t cells from chagas cardiomyopathy patients and are associated with ventricular dysfunction |
| topic | Chagas disease HLA-DRB1 cardiomyopathy cross-reactivity T-cells |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1527115/full |
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