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Gr-1⁺ Myeloid Cells Lacking T Cell Protein Tyrosine Phosphatase Inhibit Lymphocyte Proliferation by an IFN-- and Nitric Oxide-Dependent Mechanism¹

Maryse Dupuis^*, María de Jesús Ibarra-Sánchez, Michel L. Tremblay and Pascale Duplay^2,*

^* Institut National de la Recherche Scientifique-Institut Armand-Frappier, Université du Québec, Laval, Quebec, Canada; and Department of Biochemistry and McGill Cancer Center, McGill University, Montréal, Canada

The T cell protein tyrosine phosphatase is involved in the immune system regulation, as evidenced by defective function and development of several hemopoietic cell populations in T cell protein tyrosine phosphatase (TC-PTP)-deficient mice. In particular, B and T cell proliferation is greatly inhibited when total splenocytes are stimulated by LPS or anti-CD3 mAb. To define the functional defect of TC-PTP^-/- lymphocytes, we isolated T and B cells from the spleen of TC-PTP^-/- mice. We show that the proliferative response of lymphocytes was greatly increased when cultured as a purified population, indicating that an inhibitory population is present in TC-PTP^-/- spleen. However, TC-PTP^-/- lymphocytes have a 2- to 3-fold lower proliferation rate compared with TC-PTP^+/+ lymphocytes, suggesting that, as shown previously in embryonic fibroblasts, TC-PTP is involved in the control of cell cycle in lymphocytes. We have characterized phenotypically and functionally the inhibitory population present in the spleen of TC-PTP^-/- mice. We show that a Gr-1⁺-enriched cell population isolated from TC-PTP^-/- mice suppresses the CD3-induced proliferation of T cells in coculture in vitro. The specific inhibition of NO synthesis with N^G-monomethyl-L-arginine.monoacetate restored splenocyte responses, and there is a strict correlation between NO levels and the degree of suppression. Neutralization of IFN- with specific mAb almost completely abolished the inhibitory activity of Gr-1⁺ cells and concomitantly high levels of NO secretion. Moreover, inhibition of lymphocyte proliferative responses required cell-cell contact to achieve sufficient levels of NO. These findings demonstrate an important function of TC-PTP in the induction of the NO pathway that mediates inhibition of T cell proliferation.

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