1. T regulatory cell chemokine production mediates pathogenic T cell attraction and suppression
- Author
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Constadina Panagiotopoulos, Timothy J. Kieffer, Adele Y. Wang, Rusung Tan, Megan K. Levings, Anne M. Pesenacker, Jana Gillies, C. Bruce Verchere, Scott J. Patterson, Majid Mojibian, and Kim Morishita
- Subjects
Male ,0301 basic medicine ,Adoptive cell transfer ,Chemokine ,Encephalomyelitis, Autoimmune, Experimental ,Adolescent ,Receptors, CCR5 ,T cell ,Mice, Transgenic ,chemical and pharmacologic phenomena ,Biology ,T-Lymphocytes, Regulatory ,Diabetes Mellitus, Experimental ,03 medical and health sciences ,Immune system ,Antigen ,parasitic diseases ,medicine ,Animals ,Humans ,Chemokine CCL4 ,Child ,Cells, Cultured ,Cell Proliferation ,Chemokine CCL3 ,Mice, Inbred BALB C ,Infant ,hemic and immune systems ,General Medicine ,Adoptive Transfer ,Mice, Inbred C57BL ,Transplantation ,Chemotaxis, Leukocyte ,Diabetes Mellitus, Type 1 ,030104 developmental biology ,medicine.anatomical_structure ,Child, Preschool ,Immunology ,Chemokine secretion ,biology.protein ,Female ,CD8 ,Research Article - 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.
- Published
- 2016