Peripheral Generation Of Regulatory T Cells In Health And Disease
dc.contributor.advisor | Karandikar, Nitin | en |
dc.creator | Pillai, Vinodh | en |
dc.date.accessioned | 2010-07-12T18:33:20Z | en |
dc.date.accessioned | 2014-02-19T22:00:38Z | |
dc.date.available | 2010-07-12T18:33:20Z | en |
dc.date.available | 2014-02-19T22:00:38Z | |
dc.date.issued | 2007-05-23 | en |
dc.description.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. | en |
dc.format.digitalOrigin | born digital | en |
dc.format.medium | Electronic | en |
dc.format.mimetype | application/pdf | en |
dc.identifier.other | 761379862 | en |
dc.identifier.uri | http://hdl.handle.net/2152.5/598 | en |
dc.language.iso | en | en |
dc.subject | T-Lymphocytes, Regulatory | en |
dc.subject | Hepatitis C, Chronic | en |
dc.subject | Immune System Processes | en |
dc.title | Peripheral Generation Of Regulatory T Cells In Health And Disease | en |
dc.type.genre | dissertation | en |
dc.type.material | Text | en |
thesis.date.available | 2007-05-23 | en |
thesis.degree.department | en | |
thesis.degree.discipline | Immunology | en |
thesis.degree.grantor | Graduate School of Biomedical Sciences | en |
thesis.degree.level | Ph.D. | en |
thesis.degree.name | Doctor of Philosophy | en |