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dc.contributor.authorKuczma, Michal
dc.contributor.authorKopij, Magdalena
dc.contributor.authorPawlikowska, Iwona
dc.contributor.authorWang, Cong-Yi
dc.contributor.authorRempala, Grzegorz A.
dc.contributor.authorKraj, Piotr
dc.date.accessioned2012-10-26T16:26:51Z
dc.date.available2012-10-26T16:26:51Z
dc.date.issued2010-10-26en_US
dc.identifier.citationPLoS One. 2010 Oct 26; 5(10):e13623en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid21049016en_US
dc.identifier.doi10.1371/journal.pone.0013623en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/602
dc.description.abstractThe presence of Foxp3+ regulatory CD4+ T cells in tumor lesions is considered one of the major causes of ineffective immune response in cancer. It is not clear whether intratumoral Treg cells represent Treg cells pre-existing in healthy mice, or arise from tumor-specific effector CD4+ T cells and thus representing adaptive Treg cells. The generation of Treg population in tumors could be further complicated by recent evidence showing that both in humans and mice the peripheral population of Treg cells is heterogenous and consists of subsets which may differentially respond to tumor-derived antigens. We have studied Treg cells in cancer in experimental mice that express naturally selected, polyclonal repertoire of CD4+ T cells and which preserve the heterogeneity of the Treg population. The majority of Treg cells present in healthy mice maintained a stable suppressor phenotype, expressed high level of Foxp3 and an exclusive set of TCRs not used by naive CD4+ T cells. A small Treg subset, utilized TCRs shared with effector T cells and expressed a lower level of Foxp3. We show that response to tumor-derived antigens induced efficient clonal recruitment and expansion of antigen-specific effector and Treg cells. However, the population of Treg cells in tumors was dominated by cells expressing TCRs shared with effector CD4+ T cells. In contrast, Treg cells expressing an exclusive set of TCRs, that dominate in healthy mice, accounted for only a small fraction of all Treg cells in tumor lesions. Our results suggest that the Treg repertoire in tumors is generated by conversion of effector CD4+ T cells or expansion of a minor subset of Treg cells. In conclusion, successful cancer immunotherapy may depend on the ability to block upregulation of Foxp3 in effector CD4+ T cells and/or selectively inhibiting the expansion of a minor Treg subset.
dc.rightsKuczma et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.subjectResearch Articleen_US
dc.subjectImmunology/Immune Responseen_US
dc.subjectImmunology/Immunomodulationen_US
dc.subjectImmunology/Leukocyte Activationen_US
dc.subject.meshAmino Acid Sequenceen_US
dc.subject.meshAnimalsen_US
dc.subject.meshBase Sequenceen_US
dc.subject.meshCD4-Positive T-Lymphocytesen_US
dc.subject.meshCell Separationen_US
dc.subject.meshClone Cellsen_US
dc.subject.meshDNA Primersen_US
dc.subject.meshFlow Cytometryen_US
dc.subject.meshForkhead Transcription Factorsen_US
dc.subject.meshMelanoma, Experimentalen_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Transgenicen_US
dc.subject.meshMolecular Sequence Dataen_US
dc.subject.meshPolymorphism, Single-Stranded Conformationalen_US
dc.subject.meshReceptors, Antigen, T-Cellen_US
dc.subject.meshReverse Transcriptase Polymerase Chain Reactionen_US
dc.subject.meshT-Lymphocytes, Regulatoryen_US
dc.titleIntratumoral Convergence of the TCR Repertoires of Effector and Foxp3+ CD4+ T cellsen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC2964305en_US
dc.contributor.corporatenameCenter for Biotechnology and Genomic Medicine
dc.contributor.corporatenameDepartment of Biostatistics and Epidemiology
dc.contributor.corporatenameGHSU Cancer Center
refterms.dateFOA2019-04-09T22:39:21Z
html.description.abstractThe presence of Foxp3+ regulatory CD4+ T cells in tumor lesions is considered one of the major causes of ineffective immune response in cancer. It is not clear whether intratumoral Treg cells represent Treg cells pre-existing in healthy mice, or arise from tumor-specific effector CD4+ T cells and thus representing adaptive Treg cells. The generation of Treg population in tumors could be further complicated by recent evidence showing that both in humans and mice the peripheral population of Treg cells is heterogenous and consists of subsets which may differentially respond to tumor-derived antigens. We have studied Treg cells in cancer in experimental mice that express naturally selected, polyclonal repertoire of CD4+ T cells and which preserve the heterogeneity of the Treg population. The majority of Treg cells present in healthy mice maintained a stable suppressor phenotype, expressed high level of Foxp3 and an exclusive set of TCRs not used by naive CD4+ T cells. A small Treg subset, utilized TCRs shared with effector T cells and expressed a lower level of Foxp3. We show that response to tumor-derived antigens induced efficient clonal recruitment and expansion of antigen-specific effector and Treg cells. However, the population of Treg cells in tumors was dominated by cells expressing TCRs shared with effector CD4+ T cells. In contrast, Treg cells expressing an exclusive set of TCRs, that dominate in healthy mice, accounted for only a small fraction of all Treg cells in tumor lesions. Our results suggest that the Treg repertoire in tumors is generated by conversion of effector CD4+ T cells or expansion of a minor subset of Treg cells. In conclusion, successful cancer immunotherapy may depend on the ability to block upregulation of Foxp3 in effector CD4+ T cells and/or selectively inhibiting the expansion of a minor Treg subset.


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