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 5

Tregs attract CD8+ T cells in vivo via a CCL3/4-CCR5 dependent mechanism.

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Tregs attract CD8+ T cells in vivo via a CCL3/4-CCR5 dependent mechanism...
Tregs were sorted from WT, OTII, or Ccl3–/– mice, and CD8+ T cells were sorted from WT or Ccr5–/– mice. (A and B) 2 × 106 sorted OTII Tregs or Tconv cells were injected into the rear right and left feet, and a mixture of OVA 323–339 and CpG in alum was injected into the right foot only. After 18 hours, CPD-labeled WT or Ccr5–/– CD8+ T cells were injected i.v. After 40 hours, the ratio of WT or Ccr5–/– CD8+ T cells in the right and left draining inguinal lymph nodes was determined. (A) Schematic of the experimental setup. (B) Summary of the experiments, depicting the ratio of labeled WT or Ccr5–/– CD8+ T cells in the right versus left draining inguinal lymph nodes (n = 4–6 for each group, from 3 experiments), paired t test. **P < 0.01. (C and D) The right foot was injected with 1 × 106 WT or Ccl3–/– Tregs, which had been stimulated in vitro, and 2 hours later, WT or Ccr5–/– CD8+ T cells were injected i.v. (C) Schematic of the experimental setup. (D) Summary of the experiments. Each dot represents the right/left ratio from an individual mouse (n = 2–3 for each group, from 2 experiments); paired t test. *P < 0.05; **P < 0.01.