Facilitation of beta selection and modification of positive selection in the thymus of PD-1-deficient mice

H Nishimura, T Honjo, N Minato, H Nishimura, T Honjo, N Minato

Abstract

PD-1 is an immunoglobulin superfamily member bearing an immunoreceptor tyrosine-based inhibitory motif, and disruption of the PD-1 gene results in the development of lupus-like autoimmune diseases. In this study, we examined effects of the PD-1 deficiency on the thymocyte differentiation at the clonal level using T cell receptor (TCR)-beta (Vbeta8) and TCR-alpha/beta (H-Y and 2C) transgenic mice. In these TCR transgenic lines, PD-1 expression in the thymus was variably augmented, but as in the normal mice, confined largely to the CD4(-)CD8(-) thymocytes. The transgenic mice crossed with PD-1(-/)- mice in the neutral genetic backgrounds exhibited selective increase in the CD4(+)CD8(+) (DP) population with little effect on other thymocytes subsets. Similarly, the absence of PD-1 facilitated expansion of DP thymocytes in recombination activating gene (RAG)-2(-/)- mice by anti-CD3epsilon antibody injection. On the other hand, H-Y or 2C transgenic PD-1(-/)- mice with the positively selecting background showed significantly reduced efficiency for the generation of CD8(+) single positive cells bearing the transgenic TCR-alpha/beta in spite of the increased DP population. These results collectively indicate that PD-1 negatively regulates the beta selection and modulates the positive selection, and suggest that PD-1 deficiency may lead to the significant alteration of mature T cell repertoire.

Figures

Figure 1
Figure 1
Augmented expression of PD-1 in CD4−CD8− compartment in TCR transgenic lines. (a) Thymocytes from wild-type (WT), Vβ8, H-Y (H-2d), female H-Y (H-2b), and 2C (H-2b) mice were examined for PD-1 expression. Top, CD4/CD8 contour plots. Bottom, histograms for PD-1 expression in total, CD4+CD8+, and CD4− CD8− thymocytes. (b) Thymocytes from H-Y (H-2b) and 2C (H-2b) mice were examined for the expression of PD-1. The contours of CD4/CD8 profiles gated in PD-1+ (left) or PD-1− (right) fractions are shown. (c) CD69 and PD-1 expressions are shown in total thymocytes from wild-type, female H-Y (H-2b/d), and 2C (H-2b) mice. The numbers indicate percentages in gated regions. Tg, transgenic.
Figure 2
Figure 2
Effects of PD-1 deficiency on T cell development in the TCR-α/β transgenic mice in positively selecting background. (a) Thymocytes from female H-Y (H-2b) mice with or without the PD-1 mutation were analyzed for expression of CD4, CD8a, CD24, and transgenic TCR-α (T3.70). (b) Thymocytes from 2C (H-2b) mice with or without the PD-1 mutation were analyzed for expression of CD4, CD8a, transgenic TCR-α/β (1B2), CD24, CD69, and CD8β for total thymocytes (top), CD4−CD8+ (middle), and CD4+CD8+ and CD4+CD8− (bottom) subsets. Numbers indicate percentages of subsets in gated regions.

References

    1. Kisielow P., von Boehmer H. Development and selection of T cellsfacts and puzzles. Adv. Immunol. 1995;58:87–209.
    1. Adkins B., Mueller C., Okada C.Y., Reichert R.A., Weissman I.L., Spangrude G.J. Early events in T-cell maturation. Annu. Rev. Immunol. 1987;5:325–365.
    1. Godfrey D.I., Zlotnik A. Control points in early T-cell development. Immunol. Today. 1993;14:547–553.
    1. von Boehmer H., Aifantis I., Azogui O., Feinberg J., Saint Ruf C., Zober C., Garcia C., Buer J. Crucial function of the pre-T-cell receptor (TCR) in TCR beta selection, TCR beta allelic exclusion and alpha beta versus gamma delta lineage commitment. Immunol. Rev. 1998;165:111–119.
    1. von Boehmer H. Developmental biology of T cells in T cell-receptor transgenic mice. Annu. Rev. Immunol. 1990;8:531–556.
    1. von Boehmer H. Positive selection of lymphocytes. Cell. 1994;76:219–228.
    1. Nossal G.J. Negative selection of lymphocytes. Cell. 1994;76:229–239.
    1. Saint Ruf C., Ungewiss K., Groettrup M., Bruno L., Fehling H.J., von Boehmer H. Analysis and expression of a cloned pre-T cell receptor gene. Science. 1994;266:1208–1212.
    1. Mombaerts P., Clarke A.R., Rudnicki M.A., Iacomini J., Itohara S., Lafaille J.J., Wang L., Ichikawa Y., Jaenisch R., Hooper M.L. Mutations in T-cell antigen receptor genes alpha and beta block thymocyte development at different stages. Nature. 1992;360:225–231.
    1. Fehling H.J., Krotkova A., Saint Ruf C., von Boehmer H. Crucial role of the pre-T-cell receptor alpha gene in development of alpha beta but not gamma delta T cells. Nature. 1995;375:795–798.
    1. Malissen M., Gillet A., Ardouin L., Bouvier G., Trucy J., Ferrier P., Vivier E., Malissen B. Altered T cell development in mice with a targeted mutation of the CD3-epsilon gene. EMBO (Eur. Mol. Biol. Organ.) J. 1995;14:4641–4653.
    1. Agata Y., Kawasaki A., Nishimura H., Ishida Y., Tsubata T., Yagita H., Honjo T. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int. Immunol. 1996;8:765–772.
    1. Ishida Y., Agata Y., Shibahara K., Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO (Eur. Mol. Biol. Organ.) J. 1992;11:3887–3895.
    1. Nishimura H., Agata Y., Kawasaki A., Sato M., Imamura S., Minato N., Yagita H., Nakano T., Honjo T. Developmentally regulated expression of the PD-1 protein on the surface of double-negative (CD4−CD8−) thymocytes. Int. Immunol. 1996;8:773–780.
    1. Nishimura H., Nakano T., Minato N., Honjo T. Immunological studies on PD-1 deficient miceimplication of PD-1 as a negative regulator for B cell responses. Int. Immunol. 1998;10:1563–1572.
    1. Nishimura H., Nose M., Hiai H., Minato N., Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11:141–151.
    1. Uematsu Y., Ryser S., Dembic Z., Borgulya P., Krimpenfort P., Berns A., von Boehmer H., Steinmetz M. In transgenic mice the introduced functional T cell receptor beta gene prevents expression of endogenous beta genes. Cell. 1988;52:831–841.
    1. Kisielow P., Bluthmann H., Staerz U.D., Steinmetz M., von Boehmer H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature. 1988;333:742–746.
    1. Sha W.C., Nelson C.A., Newberry R.D., Kranz D.M., Russell J.H., Loh D.Y. Selective expression of an antigen receptor on CD8-bearing T lymphocytes in transgenic mice. Nature. 1988;335:271–274.
    1. Shinkai Y., Rathbun G., Lam K.P., Oltz E.M., Stewart V., Mendelsohn M., Charron J., Datta M., Young F., Stall A.M. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992;68:855–867.
    1. Teh H.S., Kisielow P., Scott B., Kishi H., Uematsu Y., Bluthmann H., von Boehmer H. Thymic major histocompatibility complex antigens and the alpha beta T-cell receptor determine the CD4/CD8 phenotype of T cells. Nature. 1988;335:229–233.
    1. Kranz D.M., Sherman D.H., Sitkovsky M.V., Pasternack M.S., Eisen H.N. Immunoprecipitation of cell surface structures of cloned cytotoxic T lymphocytes by clone-specific antisera. Proc. Natl. Acad. Sci. USA. 1984;81:573–577.
    1. von Boehmer H., Bonneville M., Ishida I., Ryser S., Lincoln G., Smith R.T., Kishi H., Scott B., Kisielow P., Tonegawa S. Early expression of a T-cell receptor beta-chain transgene suppresses rearrangement of the V gamma 4 gene segment. Proc. Natl. Acad. Sci. USA. 1988;85:9729–9732.
    1. Kishi H., Borgulya P., Scott B., Karjalainen K., Traunecker A., Kaufman J., von Boehmer H. Surface expression of the beta T cell receptor (TCR) chain in the absence of other TCR or CD3 proteins on immature T cells. EMBO (Eur. Mol. Biol. Organ.) J. 1991;10:93–100.
    1. Krotkova A., von Boehmer H., Fehling H.J. Allelic exclusion in pTα-deficient miceno evidence for cell surface expression of two T cell receptor (TCR)-β chains, but less efficient inhibition of endogenous Vβ→(D)Jβ rearrangements in the presence of a functional TCR-β transgene. J. Exp. Med. 1997;186:767–775.
    1. Buer J., Aifantis I., DiSanto J.P., Fehling H.J., von Boehmer H. Role of different T cell receptors in the development of pre-T cells. J. Exp. Med. 1997;185:1541–1547.
    1. Robey E.A., Ramsdell F., Kioussis D., Sha W., Loh D., Axel R., Fowlkes B.J. The level of CD8 expression can determine the outcome of thymic selection. Cell. 1992;69:1089–1096.
    1. Crooks M.E., Littman D.R. Disruption of T lymphocyte positive and negative selection in mice lacking the CD8 beta chain. Immunity. 1994;1:277–285.
    1. Shinkai Y., Alt F.W. CD3 epsilon-mediated signals rescue the development of CD4+CD8+ thymocytes in RAG-2−/− mice in the absence of TCR beta chain expression. Int. Immunol. 1994;6:995–1001.
    1. Lucas B., Germain R.N. Unexpectedly complex regulation of CD4/CD8 coreceptor expression supports a revised model for CD4+CD8+ thymocyte differentiation. Immunity. 1996;5:461–477.

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