Peripheral Generation of Regulatory T Cells in Health and Disease
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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.