Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation
G J Freeman, A J Long, Y Iwai, K Bourque, T Chernova, H Nishimura, L J Fitz, N Malenkovich, T Okazaki, M C Byrne, H F Horton, L Fouser, L Carter, V Ling, M R Bowman, B M Carreno, M Collins, C R Wood, T Honjo, G J Freeman, A J Long, Y Iwai, K Bourque, T Chernova, H Nishimura, L J Fitz, N Malenkovich, T Okazaki, M C Byrne, H F Horton, L Fouser, L Carter, V Ling, M R Bowman, B M Carreno, M Collins, C R Wood, T Honjo
Abstract
PD-1 is an immunoinhibitory receptor expressed by activated T cells, B cells, and myeloid cells. Mice deficient in PD-1 exhibit a breakdown of peripheral tolerance and demonstrate multiple autoimmune features. We report here that the ligand of PD-1 (PD-L1) is a member of the B7 gene family. Engagement of PD-1 by PD-L1 leads to the inhibition of T cell receptor-mediated lymphocyte proliferation and cytokine secretion. In addition, PD-1 signaling can inhibit at least suboptimal levels of CD28-mediated costimulation. PD-L1 is expressed by antigen-presenting cells, including human peripheral blood monocytes stimulated with interferon gamma, and activated human and murine dendritic cells. In addition, PD-L1 is expressed in nonlymphoid tissues such as heart and lung. The relative levels of inhibitory PD-L1 and costimulatory B7-1/B7-2 signals on antigen-presenting cells may determine the extent of T cell activation and consequently the threshold between tolerance and autoimmunity. PD-L1 expression on nonlymphoid tissues and its potential interaction with PD-1 may subsequently determine the extent of immune responses at sites of inflammation.
Figures
References
- 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.
- 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.
- Vibhakar R., Juan G., Traganos F., Darzynkiewicz Z., Finger L.R. Activation-induced expression of human programmed death-1 gene in T-lymphocytes. Exp. Cell Res. 1997;232:25–28.
- Shinohara T., Taniwaki M., Ishida Y., Kawaichi M., Honjo T. Structure and chromosomal localization of the human PD-1 gene (PDCD1) Genomics. 1994;23:704–706.
- Vivier E., Daeron M. Immunoreceptor tyrosine-based inhibition motifs. Immunol. Today. 1997;18:286–291.
- 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.
- Sperling A.I., Bluestone J.A. The complexities of T-cell costimulationCD28 and beyond. Immunol. Rev. 1996;153:155–182.
- Thompson C.B., Allison J.P. The emerging role of CTLA-4 as an immune attenuator. Immunity. 1997;7:445–450.
- Harper K., Balzano C., Rouvier E., Mattei M.-G., Luciani M.F., Golstein P. CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location. J. Immunol. 1991;147:1037–1044.
- Freeman G.J., Cardoso A.A., Boussiotis V.A., Anumanthan A., Groves R.W., Kupper T.S., Clark E.A., Nadler L.M. The BB1 monoclonal antibody recognizes both cell surface CD74 (MHC class II-associated invariant chain) as well as B7-1 (CD80), resolving the question regarding a third CD28/CTLA-4 counter receptor. J. Immunol. 1998;161:2708–2715.
- Ling V., Wu P.W., Finnerty H.F., Bean K.M., Spaulding V., Fouser L.A., Leonard J.P., Hunter S.E., Zollner R., Thomas J.L. Identification of GL50, a novel B7-like protein that functionally binds to ICOS receptor. J. Immunol. 2000;164:1653–1657.
- Blair P.J., Riley J.L., Levine B.L., Lee K.P., Craighead N., Francomano T., Perfetto S.J., Gray G.S., Carreno B.M., June C.H. CTLA-4 ligation delivers a unique signal to resting human CD4 T cells that inhibits interleukin-2 secretion but allows Bcl-XL induction. J. Immunol. 1998;160:12–15.
- Byrne M.C., Whitley M.Z., Follettie M.T. Preparation of mRNA for expression monitoring Ausubel F.M., Brent R., Kingston R.E., Moore D.D., Seidman J.G., Smith J.A., Struhl K. Current Protocols in Molecular Biology Supplement. Vol. 49 2000. 22 John Wiley & Sons, Inc; New York: 2.1–22.2.13.
- Freeman G.J., Lombard D.B., Gimmi C.D., Brod S.A., Lee K., Laning J.C., Hafler D.A., Dorf M.E., Gray G.S., Reiser H. CTLA-4 and CD28 are coexpressed in most T-cells after activation. J. Immunol. 1992;149:3795–3801.
- Boussiotis V.A., Freeman G.J., Gribben J.G., Nadler L.M. The role of B7-1/B7-2:CD28/CTLA-4 pathways in the prevention of anergy, induction of productive immunity and down-regulation of the immune response. Immunol. Rev. 1996;153:5–26.
- Dong H., Zhu G., Tamada K., Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat. Med. 1999;5:1365–1369.
- Swallow M.M., Wallin J.J., Sha W.C. B7h, a novel costimulatory homolog of B7-1 and B7-2, is induced by TNFα. Immunity. 1999;11:423–432.
- Yoshinaga S.K., Whoriskey J.S., Khare S.D., Sarmiento U., Guo J., Horan T., Shih G., Zhang M., Coccia M.A., Kohno T. T-cell co-stimulation through B7RP-1 and ICOS. Nature. 1999;402:827–832.
- Reeves R.H., Patch D., Sharpe A.H., Borriello F., Freeman G.J., Edelhoff S., Disteche C. The costimulatory genes CD80 and CD86 are linked on mouse chromosome 16 and human chromosome 3. Mamm. Genome. 1997;8:581–582.
- Henry J., Miller M.M., Pontarotti P. Structure and evolution of the extended B7 family. Immunol. Today. 1999;20:285–288.
- 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.
- Tivol E.A., Borriello F., Schweitzer A.N., Lynch W.P., Bluestone J.A., Sharpe A.H. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995;3:541–547.
- Waterhouse P., Penninger J.M., Timms E., Wakeham A., Shahinian A., Lee K.P., Thompson C.B., Griesser H., Mak T.W. Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4. Science. 1995;270:985–988.
- Nickloff B.J., Mitra R.S., Lee K., Turka L.A., Green J., Thompson C., Shimizu Y. Discordant expression of CD28 ligands, BB-1, and B7-1 on keratinocytes in vitro and psoriatic cells in vivo. Am. J. Pathology. 1993;142:1029–1040.
- Suda T., Takahashi T., Golstein P., Nagata S. Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell. 1993;75:1169–1178.
- Ikemizu S., Gilbert R.J.C., Fennelly J.A., Collins A.V., Harlos K., Jones E.Y., Stuart D.I., Davis S.J. Structure and dimerization of a soluble form of B7-1. Immunity. 2000;12:51–60.
- Fitz L.J., Morris J.C., Towler P., Long A., Burgess P., Greco R., Wang J., Gassaway R., Nickbarg E., Kovacic S. Characterization of murine Flt4 ligand/VEGF-C. Oncogene. 1997;15:613–618.
- Freedman A.S., Freeman G.J., Rhynhart K., Nadler L.M. Selective induction of B7/BB-1 on interferon-gamma stimulated monocytesa potential mechanism for amplification of T cell activation through the CD28 pathway. Cell. Immunol. 1991;137:429–437.
Source: PubMed