51. Chemokine production by regulatory T cells is required for therapeutic attenuation of autoimmunity and allograft rejection
- Author
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Anne M Pesenacker, Scott J Patterson, Adele Y Wang, Majid Mojibian, Kim Morishita, Rusung Tan, Timothy J Kieffer, C Bruce Verchere, Constadina Panagiotopoulos, and Megan K Levings
- Subjects
Immunology ,Immunology and Allergy - Abstract
Regulatory T cells (Tregs) control immune homeostasis by preventing inappropriate responses to self and non-harmful foreign antigens. Tregs use multiple mechanisms to control immune responses, all of which require Tregs to be near their targets of suppression, but how Treg-to-target proximity is controlled is unknown. We found that Tregs produce chemokines to attract CD4+ and CD8+ T cells close to their proximity in vitro and in vivo. Mouse and human lineage committed Tregs, as well as murine in vitro induced Tregs, produced CCL3 and CCL4 at message and protein level. Chemokine producing Tregs had an activated Treg phenotype with high expression of multiple proteins associated with suppressive function. Furthermore the human CCL3 and CCL4 promoter could be transactivated by FOXP3. In vitro and in vivo migration experiments indicated that CCR5 was the major receptor required by target cells. CCL3 and CCL4 deficient Tregs were impaired in their ability to prevent experimental autoimmune encephalomyelitis or islet allograft rejection, but suppressive in a standard in vitro assay. Moreover, Tregs from subjects with established type 1 were impaired in their ability to produce CCL3 and CCL4. These results demonstrate a previously unknown facet of Treg function and suggest that chemokine secretion by Tregs is a fundamental aspect of their in vivo function and therapeutic effect in autoimmunity and transplantation.
- Published
- 2016