Pillemer, Brendan Brian Louis
(2007)
Modulation of Regulatory T Cells by Cytokines.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The incidence of immunopathology is increasing; and treatments usually involve systemic immunosuppression, with significant side-effects. Regulatory T cells (Tregs) inhibit immune responses in a targeted manner, and are being studied as potential therapeutic agents. Interleukin 2 (IL-2) is among the few well-characterized modulators of Tregs. IL-2 stimulation increases Treg function, but inhibits suppression in co-cultures with T helper (Th) cells, due to dominant effects on Th cells. Characterizing cytokine modulation of Tregs is important because Treg-targeted therapy would be used primarily to treat diseases that induce cytokine production. Recent work has implicated IL-6 in the regulation of Tregs in the lung and in the pathogenesis of several diseases. We investigated the influence of IL-2 and IL-6 on Tregs, and found that they increased Treg suppressive function, proliferation, and expression of FoxP3 and CTLA4. Interestingly, both cytokines are regulated by suppressor of cytokine signaling 3 (SOCS3), and we found that unstimulated Tregs lacked SOCS3, whereas naïve Th cells expressed it abundantly. SOCS3 over-expression in Tregs inhibited proliferation, FoxP3 and CTLA4 expression, and suppressive function. Whereas IL-2 and SOCS3 seemed to act during homeostatic conditions, IL-4 is active in disease states. IL-4 is required for experimental asthma induction in mice due to its critical role in the development of Th2 cells, which protect against helminth infections. Consequently, we analyzed regulation of Tregs by IL-4 in vivo during allergic airway inflammation. Pulmonary Treg numbers were similar in tolerized mice compared to those with inflammation, and adoptive transfer of Tregs inhibited inflammation, implying that cytokines might have inhibited Treg function. However, IL-4Rα-/- Tregs, which lack the IL-4 receptor alpha chain, were less effective in reducing inflammation. In vitro, IL-4 increased Treg proliferation and maintenance of FoxP3 expression, did not alter Treg suppressive function, and increased Th cell resistance to suppression. Also, IL-4-mediated effects on Tregs and Th cells required signal transducer and activator of transcription 6 (STAT6). Therefore, IL-4 increased Treg function in vivo by enhancing Treg proliferation through a STAT6-dependent mechanism. In summary, SOCS3 may serve as a future therapeutic agent, whereas the net effect of IL-4 blockade therapy remains unclear.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
21 August 2007 |
| Date Type: |
Completion |
| Defense Date: |
17 August 2007 |
| Approval Date: |
21 August 2007 |
| Submission Date: |
17 August 2007 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
IL-2; IL-4; IL-6; regulatory T cells; SOCS3; Tregs |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-08172007-161420/, etd-08172007-161420 |
| Date Deposited: |
10 Nov 2011 19:59 |
| Last Modified: |
19 Dec 2016 14:37 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/9153 |
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