Published online before print February 16, 2007

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1006640

Received for publication October 18, 2006.
Revised January 16, 2007.
Accepted for publication January 17, 2007.

Article

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

*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

^@ To whom correspondence should be addressed. 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

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