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B220⁺ Double-Negative T Cells Suppress Polyclonal T Cell Activation by a Fas-Independent Mechanism That Involves Inhibition of IL-2 Production

Abdel Rahim A. Hamad^1,*, Abdiaziz S. Mohamood^*, Crystal J. Trujillo, Ching-Tai Huang, Emily Yuan^* and Jonathan P. Schneck^*

Departments of ^* Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and Department of Chemistry/Biochemistry, St. Mary’s University, San Antonio, TX 78228

Fas-mediated apoptosis is a key mechanism for elimination of autoreactive T cells, yet loss of function mutations in the Fas signaling pathway does not result in overt T cell-mediated autoimmunity. Furthermore, mice and humans with homozygous Fas^lpr or Fas ligand^gld mutations develop significant numbers of B220⁺ CD4^- CD8^- double-negative (DN) T cells (hereafter referred to as B220⁺ DN T cells) of poorly understood function. In this study, we show that B220⁺ DN T cells, whether generated in vitro or isolated from mutant mice, can suppress the ability of activated T cells to proliferate or produce IL-2, IL-10, and IFN-. B220⁺ DN T cells that were isolated from either lpr or gld mice were able to suppress proliferation of autologous and syngeneic CD4 T cells, showing that suppression is Fas independent. Furthermore, restoration of Fas/Fas ligand interaction did not enhance suppression. The mechanism of suppression involves inhibition of IL-2 production and its high affinity IL-2R -chain (CD25). Suppression also requires cell/cell contact and TCR activation of B220⁺ DN T cells, but not soluble cytokines. These findings suggest that B220⁺ DN T cells may be involved in controlling autoreactive T cells in the absence of Fas-mediated peripheral tolerance.

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