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CCR8 Expression Identifies CD4 Memory T Cells Enriched for FOXP3⁺ Regulatory and Th2 Effector Lymphocytes

Inflammation, Millennium Pharmaceuticals, Cambridge, MA 02139

CD4⁺ Th2 cells are important regulators of allergic inflammation. CCR8 is thought to play a role in Th2-mediated responses, however, expression of CCR8 in peripheral blood has not been fully characterized. Using a fluorescent form of the ligand selective for CCR8 (F-CCL1), we identified the leukocytes expressing CCR8 in human, monkey, and mouse peripheral blood. CCR8 expression is primarily restricted to a subset of human CD4 memory T lymphocytes (15%). Approximately 40% of CCR8⁺CD4⁺ T cells express Th2 cytokines IL-4 or IL-13 while 13% express the Th1 cytokine IFN-. In fact, 50% of all Th2, but only 5% of Th1, cells express CCR8. Upon anti-CD3/anti-CD28 mAb-mediated activation, CCR8⁺CD4⁺ T cells secrete 3- to 7-fold higher levels of IL-4, IL-5, IL-9, and IL-13 and 10- to 20-fold lower levels of IFN- or IL-17, compared with CCR8^–CD4⁺ memory T cells. Two-thirds of CCR8⁺CD4 T cells express cutaneous lymphocyte-associated Ag while the majority lack gut-homing receptors. CCR8⁺CD4⁺ cells express CCR7 and CD62L and are present in spleen and lymph nodes of mice. Approximately 25% of CCR8⁺CD4 T cells express CD25^high while 20% of CCR8⁺CD4⁺ express the T regulatory cell transcription factor FOXP3 accounting for 60% of all FOXP3-expressing CD4⁺ T cells. In conclusion, CCR8 marks a diverse subset of CD4 memory T cells enriched for T regulatory and Th2 cells which have the potential for recruitment into sites of allergic inflammation where they could participate in the induction and regulation of the allergic response.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Dulce Soler, Millennium Pharmaceuticals, 35 Landsdowne Street, Cambridge, MA 02139. E-mail address: dsoler{at}mpi.com

² Current address: Peptimmune, 64 Sidney Street, Cambridge, MA 02139.

³ Abbreviations used in this paper: T_NPM, nonpolarized memory T cell; T_CM, central memory T cell; T_EM, effector memory T cell; T_REG, regulatory T cell; CLA, cutaneous lymphoid-associated Ag; F-CCL1, fluorescently labeled CCL-1; DAPI, 4',6'-diamidino-2-phenylindole.

⁴ Current address: MedImmune, One MedImmune Way, Gaithersburg, MD 20878.

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