Gr-1+ myeloid cells lacking T cell protein tyrosine phosphatase inhibit lymphocyte proliferation by an IFN-gamma- and nitric oxide-dependent mechanism.
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-gamma 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.
Dupuis
Maryse
M
Institut National de la Recherche Scientifique-Institut Armand-Frappier, Université du Québec, Laval, Quebec, Canada.
De Jesús Ibarra-Sánchez
María
M
Tremblay
Michel L
ML
Duplay
Pascale
P
D000818:Animals; D039481:CD11b Antigen / Q000096:biosynthesis; D017252:CD3 Complex / Q000494:pharmacology; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002469:Cell Separation; D002478:Cells, Cultured; D006131:Growth Inhibitors / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000201:enzymology* / Q000276:immunology*; D009569:Nitric Oxide / Q000502:physiology*; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency* / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000201:enzymology* / Q000276:immunology
D039481:CD11b Antigen; D017252:CD3 Complex; D006131:Growth Inhibitors; D008070:Lipopolysaccharides; D011948:Receptors, Antigen, T-Cell; D009569:Nitric Oxide; D007371:Interferon-gamma; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D017027:Protein Tyrosine Phosphatases; C516653:Ptpn2 protein, mouse