T regulatory cell chemokine production mediates pathogenic T cell attraction and suppression
Scott J. Patterson, Anne M. Pesenacker, Adele Y. Wang, Jana Gillies, Majid Mojibian, Kim Morishita, Rusung Tan, Timothy J. Kieffer, C. Bruce Verchere, Constadina Panagiotopoulos, Megan K. Levings
Scott J. Patterson, Anne M. Pesenacker, Adele Y. Wang, Jana Gillies, Majid Mojibian, Kim Morishita, Rusung Tan, Timothy J. Kieffer, C. Bruce Verchere, Constadina Panagiotopoulos, Megan K. Levings
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Research Article Immunology

T regulatory cell chemokine production mediates pathogenic T cell attraction and suppression

Abstract

T regulatory cells (Tregs) control immune homeostasis by preventing inappropriate responses to self and nonharmful foreign antigens. Tregs use multiple mechanisms to control immune responses, all of which require these cells to be near their targets of suppression; however, it is not known how Treg-to-target proximity is controlled. Here, we found that Tregs attract CD4+ and CD8+ T cells by producing chemokines. Specifically, Tregs produced both CCL3 and CCL4 in response to stimulation, and production of these chemokines was critical for migration of target T cells, as Tregs from Ccl3–/– mice, which are also deficient for CCL4 production, did not promote migration. Moreover, CCR5 expression by target T cells was required for migration of these cells to supernatants conditioned by Tregs. Tregs deficient for expression of CCL3 and CCL4 were impaired in their ability to suppress experimental autoimmune encephalomyelitis or islet allograft rejection in murine models. Moreover, Tregs from subjects with established type 1 diabetes were impaired in their ability to produce CCL3 and CCL4. Together, these results demonstrate a previously unappreciated facet of Treg function and suggest that chemokine secretion by Tregs is a fundamental aspect of their therapeutic effect in autoimmunity and transplantation.

Authors

Scott J. Patterson, Anne M. Pesenacker, Adele Y. Wang, Jana Gillies, Majid Mojibian, Kim Morishita, Rusung Tan, Timothy J. Kieffer, C. Bruce Verchere, Constadina Panagiotopoulos, Megan K. Levings

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Figure 6

Ccl3–/– Tregs fail to reduce the progression and severity of EAE or to protect from islet allograft rejection.

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Ccl3–/– Tregs fail to reduce the progression and severity of EAE or to ...
(A and B) Three days before induction of EAE, WT B6 mice were injected with 2 × 106 WT or Ccl3–/– Tregs or PBS. On day 0, EAE was induced by injection of MOG35–55, CFA, and pertussis toxin. (A) The clinical EAE score was calculated daily. Data shown are the average ± SEM of the clinical scores of 6 mice per group treated in 3 separate experiments. ***P < 0.005, paired 1-way ANOVA. (B) The total number of CD4+ T cells infiltrating the CNS was determined at day 22; each symbol represents data from 1 mouse (n = 6 per group). *P < 0.05, unpaired 2-tailed Student’s t test. (C and D) Streptozocin-induced diabetic WT B6 mice were transplanted with 300 hand-picked BALB/c islets with adoptive transfer of 1 × 106 WT or Ccl3–/– Tregs or PBS. (C) Damage to pancreatic islets was monitored by reading blood glucose levels. Animals with consecutive readings of blood glucose greater than 20 mmol/l were considered diabetic. (D) Summary survival based on blood glucose levels from C (n = 5–10 per group). Results are representative of 4 separate preparations of islets and Tregs. Differences between graft survival times were assessed by Kaplan-Meier survival analysis.