{"id":{"repo_id":"utswmed","oai_identifier":"oai:utswmed-ir.tdl.org:2152.5/598"},"canonical_url":"https://search.dev.ndltd.org/etd/utswmed/oai:utswmed-ir.tdl.org:2152.5/598","repository":{"repo_id":"utswmed","name":"University of Texas Southwestern Medical Center","base_url":"https://utswmed-ir.tdl.org/server/oai/request"},"display":{"title":"Peripheral Generation of Regulatory T Cells in Health and Disease","abstract":"CD4+CD25+FOXP3+ regulatory T cells (Tregs) form an important arm of the immune system responsible for suppressing untoward immune responses. They play a role in autoimmunity, allergy, asthma, transplantation, tumors and infectious diseases. Tregs are increased in the peripheral blood of chronic hepatitis C virus-infected patients and their depletion in-vitro increases anti HCV responses when measured by a sensitive CFSE-based flow cytometric proliferation assay. The CFSE-based assay, developed and validated by my laboratory, has a greater ability to detect low frequency and low avidity type T cell responses in the chronic HCV patients that are difficult to measure using ex-vivo assays. Using this assay in a cross sectional study, I showed that anti-viral immune responses are attenuated in untreated chronic HCV patients and are increased after anti-viral treatment with Interferon and Ribavirin. Interestingly, increase in anti-viral immune responses after Treg depletion was not seen in patients who were successfully treated with interferon and ribavirin. These results suggest that anti-viral therapy may be acting by modulating anti-viral immune responses. Tregs can be thymically derived (natural Tregs) or peripherally induced (adaptive Tregs). FOXP3 expression and in-vitro suppressive activity are considered unique hallmarks of this dedicated and stable lineage of regulatory cells. Initial evidence indicated that it is a specific marker of natural Tregs. It was thought that FOXP3+ T cells cannot arise in the periphery from na?CD4+CD25- T cells. However, using allostimulation of CFSE stained T cells and polycolor flow cytometry, I showed that virtually all human CD4+CD25-FOXP3- T cells and CD8+CD25-FOXP3- T cells attain a transient FOXP3+CD25+ state during activation. In this state of activation, these cells possess the classic phenotype of Tregs, in that they express similar markers and inhibit in-vitro proliferation of autologous CD4+CD25- T cells. This state is characterized by suppressed IFN-gamma production and robust TNF-alpha and IL-10 production. Interestingly, the great majority of the activated cells eventually downregulate FOXP3 expression, with a concomitant drop in suppressive ability. However some of the FOXP3+ T cells continue to maintain FOXP3 expression suggesting that activation might be a mechanism of producing FOXP3+ Regulatory T cells in the periphery during viral infections like chronic HCV infection. Transient FOXP3 expression in activated T cells might also be a mechanism of fine tuning excessive immune activation. These results show that, in humans, FOXP3 expression and Treg functionality are not exclusive features of a stable or unique lineage of T cells, but may also be a transient state attained by almost all T cells. These results warrant caution in interpreting human studies using FOXP3 and suppressive activity as readouts and suggest that attempts to induce " Tregs" may paradoxically result in induction of effector T cells, unless stability is confirmed.","abstract_html":"CD4+CD25+FOXP3+ regulatory T cells (Tregs) form an important arm of the immune system responsible for suppressing untoward immune responses. They play a role in autoimmunity, allergy, asthma, transplantation, tumors and infectious diseases. Tregs are increased in the peripheral blood of chronic hepatitis C virus-infected patients and their depletion in-vitro increases anti HCV responses when measured by a sensitive CFSE-based flow cytometric proliferation assay. The CFSE-based assay, developed and validated by my laboratory, has a greater ability to detect low frequency and low avidity type T cell responses in the chronic HCV patients that are difficult to measure using ex-vivo assays. Using this assay in a cross sectional study, I showed that anti-viral immune responses are attenuated in untreated chronic HCV patients and are increased after anti-viral treatment with Interferon and Ribavirin. Interestingly, increase in anti-viral immune responses after Treg depletion was not seen in patients who were successfully treated with interferon and ribavirin. These results suggest that anti-viral therapy may be acting by modulating anti-viral immune responses. Tregs can be thymically derived (natural Tregs) or peripherally induced (adaptive Tregs). FOXP3 expression and in-vitro suppressive activity are considered unique hallmarks of this dedicated and stable lineage of regulatory cells. Initial evidence indicated that it is a specific marker of natural Tregs. It was thought that FOXP3+ T cells cannot arise in the periphery from na?CD4+CD25- T cells. However, using allostimulation of CFSE stained T cells and polycolor flow cytometry, I showed that virtually all human CD4+CD25-FOXP3- T cells and CD8+CD25-FOXP3- T cells attain a transient FOXP3+CD25+ state during activation. In this state of activation, these cells possess the classic phenotype of Tregs, in that they express similar markers and inhibit in-vitro proliferation of autologous CD4+CD25- T cells. This state is characterized by suppressed IFN-gamma production and robust TNF-alpha and IL-10 production. Interestingly, the great majority of the activated cells eventually downregulate FOXP3 expression, with a concomitant drop in suppressive ability. However some of the FOXP3+ T cells continue to maintain FOXP3 expression suggesting that activation might be a mechanism of producing FOXP3+ Regulatory T cells in the periphery during viral infections like chronic HCV infection. Transient FOXP3 expression in activated T cells might also be a mechanism of fine tuning excessive immune activation. These results show that, in humans, FOXP3 expression and Treg functionality are not exclusive features of a stable or unique lineage of T cells, but may also be a transient state attained by almost all T cells. These results warrant caution in interpreting human studies using FOXP3 and suppressive activity as readouts and suggest that attempts to induce " Tregs" may paradoxically result in induction of effector T cells, unless stability is confirmed.","abstract_has_math":false,"creators":["Pillai, Vinodh"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Karandikar, Nitin J."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2010,"date_issued":"2010-07-12T18:33:20Z","date_published":"2010-07-12T18:33:20Z","updated_at":"2026-07-24T05:52:31Z","subjects":["T-Lymphocytes, Regulatory","Hepatitis C, Chronic","Immune System Phenomena"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["761379862"],"render_values":[{"text":"761379862","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/2152.5/598","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Karandikar, Nitin J."]},{"key":"dc:creator","label":"Author","values":["Pillai, Vinodh"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2010-07-12T18:33:20Z","2007-05-23"]},{"key":"dc:type","label":"Dc Type","values":["Thesis","Text","dissertation"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["T-Lymphocytes, Regulatory","Hepatitis C, Chronic","Immune System Phenomena"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2152.5/598","761379862"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["CD4+CD25+FOXP3+ regulatory T cells (Tregs) form an important arm of the immune system responsible for suppressing untoward immune responses. They play a role in autoimmunity, allergy, asthma, transplantation, tumors and infectious diseases. Tregs are increased in the peripheral blood of chronic hepatitis C virus-infected patients and their depletion in-vitro increases anti HCV responses when measured by a sensitive CFSE-based flow cytometric proliferation assay. The CFSE-based assay, developed and validated by my laboratory, has a greater ability to detect low frequency and low avidity type T cell responses in the chronic HCV patients that are difficult to measure using ex-vivo assays. Using this assay in a cross sectional study, I showed that anti-viral immune responses are attenuated in untreated chronic HCV patients and are increased after anti-viral treatment with Interferon and Ribavirin. Interestingly, increase in anti-viral immune responses after Treg depletion was not seen in patients who were successfully treated with interferon and ribavirin. These results suggest that anti-viral therapy may be acting by modulating anti-viral immune responses. Tregs can be thymically derived (natural Tregs) or peripherally induced (adaptive Tregs). FOXP3 expression and in-vitro suppressive activity are considered unique hallmarks of this dedicated and stable lineage of regulatory cells. Initial evidence indicated that it is a specific marker of natural Tregs. It was thought that FOXP3+ T cells cannot arise in the periphery from na?CD4+CD25- T cells. However, using allostimulation of CFSE stained T cells and polycolor flow cytometry, I showed that virtually all human CD4+CD25-FOXP3- T cells and CD8+CD25-FOXP3- T cells attain a transient FOXP3+CD25+ state during activation. In this state of activation, these cells possess the classic phenotype of Tregs, in that they express similar markers and inhibit in-vitro proliferation of autologous CD4+CD25- T cells. This state is characterized by suppressed IFN-gamma production and robust TNF-alpha and IL-10 production. Interestingly, the great majority of the activated cells eventually downregulate FOXP3 expression, with a concomitant drop in suppressive ability. However some of the FOXP3+ T cells continue to maintain FOXP3 expression suggesting that activation might be a mechanism of producing FOXP3+ Regulatory T cells in the periphery during viral infections like chronic HCV infection. Transient FOXP3 expression in activated T cells might also be a mechanism of fine tuning excessive immune activation. These results show that, in humans, FOXP3 expression and Treg functionality are not exclusive features of a stable or unique lineage of T cells, but may also be a transient state attained by almost all T cells. These results warrant caution in interpreting human studies using FOXP3 and suppressive activity as readouts and suggest that attempts to induce " Tregs" may paradoxically result in induction of effector T cells, unless stability is confirmed."]},{"key":"dc:format","label":"Dc Format","values":["Electronic","application/pdf","born digital"]},{"key":"dc:title","label":"Title","values":["Peripheral Generation of Regulatory T Cells in Health and Disease"]}]}],"canonical_facts":{"dc:contributor":["Karandikar, Nitin J."],"dc:creator":["Pillai, Vinodh"],"dc:date":["2010-07-12T18:33:20Z","2007-05-23"],"dc:description":["CD4+CD25+FOXP3+ regulatory T cells (Tregs) form an important arm of the immune system responsible for suppressing untoward immune responses. They play a role in autoimmunity, allergy, asthma, transplantation, tumors and infectious diseases. Tregs are increased in the peripheral blood of chronic hepatitis C virus-infected patients and their depletion in-vitro increases anti HCV responses when measured by a sensitive CFSE-based flow cytometric proliferation assay. The CFSE-based assay, developed and validated by my laboratory, has a greater ability to detect low frequency and low avidity type T cell responses in the chronic HCV patients that are difficult to measure using ex-vivo assays. Using this assay in a cross sectional study, I showed that anti-viral immune responses are attenuated in untreated chronic HCV patients and are increased after anti-viral treatment with Interferon and Ribavirin. Interestingly, increase in anti-viral immune responses after Treg depletion was not seen in patients who were successfully treated with interferon and ribavirin. These results suggest that anti-viral therapy may be acting by modulating anti-viral immune responses. Tregs can be thymically derived (natural Tregs) or peripherally induced (adaptive Tregs). FOXP3 expression and in-vitro suppressive activity are considered unique hallmarks of this dedicated and stable lineage of regulatory cells. Initial evidence indicated that it is a specific marker of natural Tregs. It was thought that FOXP3+ T cells cannot arise in the periphery from na?CD4+CD25- T cells. However, using allostimulation of CFSE stained T cells and polycolor flow cytometry, I showed that virtually all human CD4+CD25-FOXP3- T cells and CD8+CD25-FOXP3- T cells attain a transient FOXP3+CD25+ state during activation. In this state of activation, these cells possess the classic phenotype of Tregs, in that they express similar markers and inhibit in-vitro proliferation of autologous CD4+CD25- T cells. This state is characterized by suppressed IFN-gamma production and robust TNF-alpha and IL-10 production. Interestingly, the great majority of the activated cells eventually downregulate FOXP3 expression, with a concomitant drop in suppressive ability. However some of the FOXP3+ T cells continue to maintain FOXP3 expression suggesting that activation might be a mechanism of producing FOXP3+ Regulatory T cells in the periphery during viral infections like chronic HCV infection. Transient FOXP3 expression in activated T cells might also be a mechanism of fine tuning excessive immune activation. These results show that, in humans, FOXP3 expression and Treg functionality are not exclusive features of a stable or unique lineage of T cells, but may also be a transient state attained by almost all T cells. These results warrant caution in interpreting human studies using FOXP3 and suppressive activity as readouts and suggest that attempts to induce " Tregs" may paradoxically result in induction of effector T cells, unless stability is confirmed."],"dc:format":["Electronic","application/pdf","born digital"],"dc:identifier":["https://hdl.handle.net/2152.5/598","761379862"],"dc:language":["en"],"dc:subject":["T-Lymphocytes, Regulatory","Hepatitis C, Chronic","Immune System Phenomena"],"dc:title":["Peripheral Generation of Regulatory T Cells in Health and Disease"],"dc:type":["Thesis","Text","dissertation"]},"updated_at":"2026-07-24T05:52:31Z"}