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Published online before print February 16, 2007

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(Journal of Leukocyte Biology. 2007;81:1205-1212.)
© 2007 by Society for Leukocyte Biology

Mycobacteria-induced Gr-1⁺ subsets from distinct myeloid lineages have opposite effects on T cell expansion

Therese A. Dietlin^*, Florence M. Hofman^*, Brett T. Lund^*, Wendy Gilmore^*, Stephen A. Stohlman and Roel C. van der Veen^*,1

^* Departments of Neurology and Pathology, University of Southern California Keck School of Medicine, Los Angeles, California, USA; and
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA

¹ Correspondence: Department of Neurology, University of Southern California Keck School of Medicine, MCA 245, 1333 San Pablo Street, Los Angeles, CA 90033, USA. E-mail: vanderve{at}usc.edu

ABSTRACT

Similar to the regulation of vasodilation, the balance between NO and superoxide (O₂^–) regulates expansion of activated T cells in mice. Reduction of suppressive NO levels by O₂^– is essential for T cell expansion and development of autoimmunity. In mice primed with heat-killed Mycobacterium, a splenocyte population positive for Gr-1 (Ly-6G/C) is the exclusive source of both immunoregulatory free radicals. Distinct Gr-1⁺ cell subpopulations were separated according to Ly-6G expression. In culture with activated T cells, predominantly monocytic Ly-6G^– Gr-1⁺ cells produced T cell-inhibitory NO but no O₂^–. However, mostly granulocytic Ly-6G⁺ cells produced O₂^– simultaneously but had no measurable effect on proliferation. Recombination of the two purified Gr-1⁺ subpopulations restored controlled regulation of T cell proliferation through NO and O₂^– interaction. Coculture of p47^phox–/– and inducible NO synthase^–/– Gr-1⁺ cells confirmed this intercellular interaction. These data suggest that bacterial products induce development of distinct Gr-1⁺ myeloid lineages, which upon stimulation by activated T cells, interact via their respective free radical products to modulate T cell expansion.

Key Words: nitric oxide • superoxide • myeloid suppressor cells • granulocytes • monocytes