The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses.

T cell activation is dependent upon signals delivered through the antigen-specific T cell receptor and accessory receptors on the T cell. A primary costimulatory signal is delivered through the CD28 receptor after engagement of its ligands, B7-1 (CD80) or B7-2 (CD86). Engagement of CTLA-4 (CD152) by the same B7-1 or B7-2 ligands results in attenuation of T cells responses. Recently, molecular homologs of CD28 and CTLA-4 receptors and their B7-like ligands have been identified. ICOS is a CD28-like costimulatory receptor with a unique B7-like ligand. PD-1 is an inhibitory receptor, with two B7-like ligands. Additional members of B7 and CD28 gene families have been proposed. Integration of signals through this family of costimulatory and inhibitory receptors and their ligands is critical for activation of immune responses and tolerance. Understanding these pathways will allow development of new strategies for therapeutic intervention in immune-mediated diseases.

[1]  J. Bluestone,et al.  Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. , 1995, Immunity.

[2]  S. Lehar,et al.  The CD28-related molecule ICOS is required for effective T cell-dependent immune responses. , 2000, Immunity.

[3]  R. Ceriani,et al.  Cloning and sequence analysis of human butyrophilin reveals a potential receptor function. , 1996, Biochimica et biophysica acta.

[4]  V. Kuchroo,et al.  CD28/B7 costimulation: a review. , 1998, Critical reviews in immunology.

[5]  R. Flavell,et al.  Mice deficient for the CD40 ligand. , 1994, Immunity.

[6]  T. Honjo,et al.  PD-1: an inhibitory immunoreceptor involved in peripheral tolerance. , 2001, Trends in immunology.

[7]  A. Billiau,et al.  Accelerated collagen-induced arthritis in IFN-gamma receptor-deficient mice. , 1997, Journal of immunology.

[8]  Federica Sallusto,et al.  Follicular B Helper T Cells Express Cxc Chemokine Receptor 5, Localize to B Cell Follicles, and Support Immunoglobulin Production , 2000, The Journal of experimental medicine.

[9]  Andreas Hutloff,et al.  ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28 , 1999, Nature.

[10]  D. Paslier,et al.  Physical mapping of the human and mouse MOG gene at the distal end of the MHC class Ib region , 2004, Immunogenetics.

[11]  P. Pontarotti,et al.  Structure and evolution of the extended B7 family. , 1999, Immunology today.

[12]  G. Freeman,et al.  Mouse Inducible Costimulatory Molecule (ICOS) Expression Is Enhanced by CD28 Costimulation and Regulates Differentiation of CD4+ T Cells1 , 2000, The Journal of Immunology.

[13]  J. Bonnefoy,et al.  Soluble CD86 is a costimulatory molecule for human T lymphocytes. , 2000, Immunity.

[14]  D I Stuart,et al.  Structure and dimerization of a soluble form of B7-1. , 2000, Immunity.

[15]  A. Oxenius,et al.  Inducible Costimulator Protein (Icos) Controls T Helper Cell Subset Polarization after Virus and Parasite Infection , 2000, The Journal of experimental medicine.

[16]  Yan Zhang,et al.  Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses , 2001, Nature.

[17]  P. Linsley,et al.  Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways , 1996, Nature.

[18]  C. Disteche,et al.  Characterization of the murine B7-1 genomic locus reveals an additional exon encoding an alternative cytoplasmic domain and a chromosomal location of chromosome 16, band B5. , 1994, Journal of immunology.

[19]  Paul W. Wu,et al.  Assembly and annotation of human chromosome 2q33 sequence containing the CD28, CTLA4, and ICOS gene cluster: analysis by computational, comparative, and microarray approaches. , 2001, Genomics.

[20]  T. Honjo,et al.  Facilitation of β Selection and Modification of Positive Selection in the Thymus of Pd-1–Deficient Mice , 2000, The Journal of experimental medicine.

[21]  A. Sharpe,et al.  CD28-independent Costimulation of T Cells in Alloimmune Responses1 , 2001, The Journal of Immunology.

[22]  K. Tezuka,et al.  AILIM/ICOS: a novel lymphocyte adhesion molecule. , 2000, International immunology.

[23]  P. Linsley,et al.  Molecular modeling of CD28 and three-dimensional analysis of residue conservation in the CD28/CD152 family. , 1997, Journal of molecular graphics & modelling.

[24]  T. Mak,et al.  Regulation of T Cell Receptor Signaling by Tyrosine Phosphatase SYP Association with CTLA-4 , 1996, Science.

[25]  R. Hardy,et al.  The human PD-1 gene: complete cDNA, genomic organization, and developmentally regulated expression in B cell progenitors. , 1997, Gene.

[26]  W. Sha,et al.  B7h, a novel costimulatory homolog of B7.1 and B7.2, is induced by TNFalpha. , 1999, Immunity.

[27]  P. Linsley,et al.  CD80 (B7-1) Binds Both CD28 and CTLA-4 with a Low Affinity and Very Fast Kinetics , 1997, The Journal of experimental medicine.

[28]  M. Hattori,et al.  The DNA sequence of human chromosome 21 , 2000, Nature.

[29]  Paul M. Allen,et al.  Proline Residues in Cd28 and the Src Homology (Sh)3 Domain of Lck Are Required for T Cell Costimulation , 1999, The Journal of experimental medicine.

[30]  Paul W. Wu,et al.  Differential Expression of Inducible Costimulator-Ligand Splice Variants: Lymphoid Regulation of Mouse GL50-B and Human GL50 Molecules , 2001, The Journal of Immunology.

[31]  J. Allison,et al.  ICOS co-stimulatory receptor is essential for T-cell activation and function , 2001, Nature.

[32]  T. Honjo,et al.  Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. , 1996, International immunology.

[33]  J. Egen,et al.  CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. , 2001, Annual review of immunology.

[34]  K. Bennett,et al.  Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement. , 1996, Immunity.

[35]  R. Mitchell,et al.  B7-dependent T-cell costimulation in mice lacking CD28 and CTLA4. , 2001, Journal of Clinical Investigation.

[36]  T. Mak,et al.  T-cell co-stimulation through B7RP-1 and ICOS , 1999, Nature.

[37]  U. Dianzani,et al.  The T cell activation molecule H4 and the CD28‐like molecule ICOS are identical , 2000, European journal of immunology.

[38]  L. Lanier,et al.  Immune inhibitory receptors. , 2000, Science.

[39]  Suneet Agarwal,et al.  Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. , 1998, Immunity.

[40]  H. Lassmann,et al.  Butyrophilin, a Milk Protein, Modulates the Encephalitogenic T Cell Response to Myelin Oligodendrocyte Glycoprotein in Experimental Autoimmune Encephalomyelitis1 , 2000, The Journal of Immunology.

[41]  J. Bluestone,et al.  B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. , 2000, Immunity.

[42]  Paul W. Wu,et al.  Cutting Edge: Identification of GL50, a Novel B7-Like Protein That Functionally Binds to ICOS Receptor , 2000, The Journal of Immunology.

[43]  E. Shevach.  Regulatory T cells in autoimmmunity*. , 2000, Annual review of immunology.

[44]  J. Allison,et al.  CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells , 1996, The Journal of experimental medicine.

[45]  T. Sullivan,et al.  Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells. , 1997, Immunity.

[46]  E. Simpson,et al.  B7-1 and B7-2 have overlapping, critical roles in immunoglobulin class switching and germinal center formation. , 1997, Immunity.

[47]  J. Allison,et al.  CTLA-4-Mediated inhibition of early events of T cell proliferation. , 1999, Journal of immunology.

[48]  K P Lee,et al.  Differential T cell costimulatory requirements in CD28-deficient mice. , 1993, Science.

[49]  J. Gutiérrez-Ramos,et al.  Importance of ICOS–B7RP-1 costimulation in acute and chronic allograft rejection , 2001, Nature Immunology.

[50]  E. Clark,et al.  Characterization of Human Inducible Costimulator Ligand Expression and Function1 , 2000, The Journal of Immunology.

[51]  R J Armitage,et al.  Humoral immune responses in CD40 ligand-deficient mice , 1994, The Journal of experimental medicine.

[52]  S. Davis,et al.  LICOS, a primordial costimulatory ligand? , 2000, Current Biology.

[53]  K. Artzt,et al.  Myelin/oligodendrocyte glycoprotein is a member of a subset of the immunoglobulin superfamily encoded within the major histocompatibility complex. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[54]  P. Loetscher,et al.  Cxc Chemokine Receptor 5 Expression Defines Follicular Homing T Cells with B Cell Helper Function , 2000, The Journal of experimental medicine.

[55]  K. Sakamaki,et al.  Identification and characterization of rat AILIM/ICOS, a novel T-cell costimulatory molecule, related to the CD28/CTLA4 family. , 2000, Biochemical and biophysical research communications.

[56]  R. Kroczek,et al.  ICOS is critical for T helper cell–mediated lung mucosal inflammatory responses , 2001, Nature Immunology.

[57]  T. Pawson,et al.  ICOS is essential for effective T-helper-cell responses , 2001, Nature.

[58]  P. Linsley,et al.  Extending the B7 (CD80) gene family , 1994, Protein science : a publication of the Protein Society.

[59]  T. Honjo,et al.  Induced expression of PD‐1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. , 1992, The EMBO journal.

[60]  T. Honjo,et al.  Developmentally regulated expression of the PD-1 protein on the surface of double-negative (CD4-CD8-) thymocytes. , 1996, International immunology.

[61]  G. Freeman,et al.  ICOS is critical for CD40-mediated antibody class switching , 2001, Nature.

[62]  S. Beck,et al.  The cluster of BTN genes in the extended major histocompatibility complex. , 2001, Genomics.

[63]  G. Freeman,et al.  Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation , 2000, The Journal of experimental medicine.

[64]  T. Honjo,et al.  Immunological studies on PD-1 deficient mice: implication of PD-1 as a negative regulator for B cell responses. , 1998, International immunology.

[65]  H. Ochs,et al.  Induction, binding specificity and function of human ICOS , 2000, European journal of immunology.

[66]  G. Zhu,et al.  B7-H3: A costimulatory molecule for T cell activation and IFN-γ production , 2001, Nature Immunology.

[67]  T. Owens,et al.  Interferon‐γ confers resistance to experimental allergic encephalomyelitis , 1996, European journal of immunology.

[68]  C. Thompson,et al.  CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL. , 1995, Immunity.

[69]  K. Okkenhaug,et al.  A point mutation in CD28 distinguishes proliferative signals from survival signals , 2001, Nature Immunology.

[70]  G. Freeman,et al.  Differential expression of alternate mB7-2 transcripts. , 1995, Journal of immunology.

[71]  D. Pardoll,et al.  B7-Dc, a New Dendritic Cell Molecule with Potent Costimulatory Properties for T Cells , 2001, The Journal of experimental medicine.

[72]  M. Taniwaki,et al.  Structure and chromosomal localization of the human PD-1 gene (PDCD1). , 1994, Genomics.

[73]  A. Shaw,et al.  Cutting Edge: Distinct Motifs Within CD28 Regulate T Cell Proliferation and Induction of Bcl-XL1 , 2001, The Journal of Immunology.

[74]  J. Bluestone,et al.  Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. , 2001, Annual review of immunology.

[75]  N. Nomura,et al.  Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. , 1997, DNA research : an international journal for rapid publication of reports on genes and genomes.

[76]  T. Okazaki,et al.  Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. , 2001, Science.

[77]  J. Gutiérrez-Ramos,et al.  The costimulatory molecule ICOS plays an important role in the immunopathogenesis of EAE , 2001, Nature Immunology.

[78]  H. Griesser,et al.  Lymphoproliferative Disorders with Early Lethality in Mice Deficient in Ctla-4 , 1995, Science.

[79]  O. Witzke,et al.  Critical Role for IL-4 in the Development of Transplant Arteriosclerosis in the Absence of CD40-CD154 Costimulation1 , 2001, The Journal of Immunology.

[80]  R. Wolff,et al.  A 1.1-Mb transcript map of the hereditary hemochromatosis locus. , 1997, Genome research.

[81]  W. Sha,et al.  Enhancement of CD8+ T Cell Responses by ICOS/B7h Costimulation1 , 2001, The Journal of Immunology.

[82]  G. Zhu,et al.  Costimulation of T cells by B7-H2, a B7-like molecule that binds ICOS , 2000 .

[83]  G. Freeman,et al.  PD-L2 is a second ligand for PD-1 and inhibits T cell activation , 2001, Nature Immunology.

[84]  T. Honjo,et al.  Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. , 1999, Immunity.

[85]  I. Mather,et al.  A review of the molecular and cellular biology of butyrophilin, the major protein of bovine milk fat globule membrane. , 1993, Journal of dairy science.

[86]  A. Billiau,et al.  Enhancement of experimental allergic encephalomyelitis in mice by antibodies against IFN-gamma. , 1988, Journal of Immunology.

[87]  J. Allison,et al.  Thymocyte development is normal in CTLA-4-deficient mice. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[88]  V. Kuchroo,et al.  Studies in B7-Deficient Mice Reveal a Critical Role for B7 Costimulation in Both Induction and Effector Phases of Experimental Autoimmune Encephalomyelitis , 1999, The Journal of experimental medicine.

[89]  G. Zhu,et al.  B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion , 1999, Nature Medicine.

[90]  H. Weiner,et al.  IL-10 is critical in the regulation of automimmune encephalomyelitis as demonstrated by studies of IL-10 and IL-4 deficient and transgenic mice , 1998, Journal of Neuroimmunology.

[91]  R. Flavell,et al.  Cutting Edge: Critical Role of Inducible Costimulator in Germinal Center Reactions1 , 2001, The Journal of Immunology.

[92]  J. Bluestone,et al.  CTLA-4 ligation blocks CD28-dependent T cell activation [published erratum appears in J Exp Med 1996 Jul 1;184(1):301] , 1996, The Journal of experimental medicine.

[93]  A. Fedorov,et al.  Structural basis for co-stimulation by the human CTLA-4/B7-2 complex , 2001, Nature.

[94]  T. Boone,et al.  Characterization of a new human B7-related protein: B7RP-1 is the ligand to the co-stimulatory protein ICOS. , 2000, International immunology.

[95]  P. Blair,et al.  ICOS Costimulation Requires IL-2 and Can Be Prevented by CTLA-4 Engagement1 , 2001, The Journal of Immunology.

[96]  H. Himmelbauer,et al.  Molecular cloning and characterization of murine ICOS and identification of B7h as ICOS ligand , 2000, European journal of immunology.

[97]  Christopher C. Goodnow,et al.  A genomic view of immunology , 2001, Nature.