Enhancement of HIV-Specific CD8 T Cell Responses by Dual Costimulation with CD80 and CD137L1

HIV-specific CD8 T cell responses are defective in chronic HIV infection. In this study, we report that costimulation with either CD137L (4-1BBL) or CD80 (B7.1) enhanced the Ag-specific expansion and acquisition of effector function by HIV-specific memory CD8 T cells. Ag-specific T cells from recently infected donors showed maximal expansion with single costimulatory molecules. Dual costimulation of T cells from recently infected donors or from healthy donors responding to influenza epitopes led to enhanced responses when the accumulation of cytokines was measured. However, accumulation of regulatory cytokines, particularly IFN-γ, led to inhibition of further Ag-specific CD8 T cell expansion in the cultures. This inhibition was relieved by neutralization of IFN-γ or of IFN-γ, TNF, and IL-10. Thus, strong costimulation of T cells in vitro can lead to induction of regulatory cytokines at levels that limit further T cell expansion. In marked contrast, T cells from long-term (>4 years) infected HIV+ donors exhibited reduced Ag-specific CD8 T cell expansion, reduced CD4 T cell responses, and minimal cytokine accumulation. Dual costimulation with both 4-1BBL and B7.1 enhanced responses of T cells from long-term infected subjects to a level similar to that obtained with T cells from early in HIV infection. Experiments with purified CD8 T cells showed that B7.1 and 4-1BBL could act directly and synergistically on CD8 T cells. Taken together, these data suggest that 4-1BBL and B7.1 have additive or synergistic effects on HIV-specific CD8 T cell responses and represent a promising combination for therapeutic vaccination for HIV.

[1]  J. Whitton,et al.  Interferon-γ acts directly on CD8+ T cells to increase their abundance during virus infection , 2005, The Journal of experimental medicine.

[2]  Hye-young Park,et al.  4-1BB-mediated immunotherapy of rheumatoid arthritis , 2004, Nature Medicine.

[3]  Galit Alter,et al.  Loss of HIV-1–specific CD8+ T Cell Proliferation after Acute HIV-1 Infection and Restoration by Vaccine-induced HIV-1–specific CD4+ T Cells , 2004, The Journal of experimental medicine.

[4]  M. Bevan,et al.  CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection , 2004, Nature Immunology.

[5]  T. Watts,et al.  Costimulatory ligand 4-1BBL (CD137L) as an efficient adjuvant for human antiviral cytotoxic T cell responses. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[6]  E. Bertram,et al.  A Switch in Costimulation from CD28 to 4-1BB during Primary versus Secondary CD8 T Cell Response to Influenza In Vivo1 , 2004, The Journal of Immunology.

[7]  Z. Grossman,et al.  HIV-1 Viremia Prevents the Establishment of Interleukin 2–producing HIV-specific Memory CD4+ T Cells Endowed with Proliferative Capacity , 2003, The Journal of experimental medicine.

[8]  M. Croft.  Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? , 2003, Nature Reviews Immunology.

[9]  C. Takahashi,et al.  Effector CD8 T cells possess suppressor function after 4-1BB and Toll-like receptor triggering , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Hao Shen,et al.  Requirement for CD4 T Cell Help in Generating Functional CD8 T Cell Memory , 2003, Science.

[11]  M. Bevan,et al.  Defective CD8 T Cell Memory Following Acute Infection Without CD4 T Cell Help , 2003, Science.

[12]  Urs Christen,et al.  CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes , 2003, Nature.

[13]  T. Watts,et al.  Costimulation of human CD28– T cells by 4‐1BB ligand , 2003, European journal of immunology.

[14]  S. Rowland-Jones,et al.  Premature ageing of the immune system: the cause of AIDS? , 2002, Trends in immunology.

[15]  Sujung Park,et al.  4-1BB Promotes the Survival of CD8+ T Lymphocytes by Increasing Expression of Bcl-xL and Bfl-11 , 2002, The Journal of Immunology.

[16]  H. Broxmeyer,et al.  Role of 4-1BB (CD137) in the functional activation of cord blood CD28(-)CD8(+) T cells. , 2002, Blood.

[17]  M. Croft,et al.  Defective T Cell Priming Associated with Aging Can Be Rescued by Signaling Through 4-1BB (CD137)1 , 2002, The Journal of Immunology.

[18]  Lieping Chen,et al.  Signaling Through NK Cell-Associated CD137 Promotes Both Helper Function for CD8+ Cytolytic T Cells and Responsiveness to IL-2 But Not Cytolytic Activity1 , 2002, The Journal of Immunology.

[19]  C. Hallahan,et al.  HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors , 2002, Nature Immunology.

[20]  A. Galy,et al.  4-1BB co-stimulation enhances human CD8(+) T cell priming by augmenting the proliferation and survival of effector CD8(+) T cells. , 2002, International immunology.

[21]  A. Telenti,et al.  Analysis of HIV-1- and CMV-specific memory CD4 T-cell responses during primary and chronic infection. , 2002, Blood.

[22]  C. Thompson,et al.  The CD28 signaling pathway regulates glucose metabolism. , 2002, Immunity.

[23]  T. Watts,et al.  4-1BB Ligand-Mediated Costimulation of Human T Cells Induces CD4 and CD8 T Cell Expansion, Cytokine Production, and the Development of Cytolytic Effector Function1 , 2002, The Journal of Immunology.

[24]  Z. Grossman,et al.  HIV preferentially infects HIV-specific CD4+ T cells , 2002, Nature.

[25]  Lieping Chen,et al.  Cutting Edge: Expression of Functional CD137 Receptor by Dendritic Cells1 , 2002, The Journal of Immunology.

[26]  E. Bertram,et al.  Temporal Segregation of 4-1BB Versus CD28-Mediated Costimulation: 4-1BB Ligand Influences T Cell Numbers Late in the Primary Response and Regulates the Size of the T Cell Memory Response Following Influenza Infection1 , 2002, The Journal of Immunology.

[27]  D. Richman,et al.  Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections , 2002, Nature Medicine.

[28]  K. Takeda,et al.  Expression and function of 4-1BB and 4-1BB ligand on murine dendritic cells. , 2002, International immunology.

[29]  G. Freeman,et al.  The B7–CD28 superfamily , 2002, Nature Reviews Immunology.

[30]  David Allman,et al.  Ex vivo expansion of polyclonal and antigen-specific cytotoxic T lymphocytes by artificial APCs expressing ligands for the T-cell receptor, CD28 and 4-1BB , 2002, Nature Biotechnology.

[31]  R. V. van Lier,et al.  Constitutive CD27/CD70 interaction induces expansion of effector-type T cells and results in IFNgamma-mediated B cell depletion. , 2001, Immunity.

[32]  G. Zhu,et al.  Progressive Depletion of Peripheral B Lymphocytes in 4-1BB (CD137) Ligand/I-Eα-Transgenic Mice1 , 2001, The Journal of Immunology.

[33]  S. Rowland-Jones,et al.  Skewed maturation of memory HIV-specific CD8 T lymphocytes , 2001, Nature.

[34]  E. Rosenberg,et al.  Immune control of HIV-1 after early treatment of acute infection , 2000, Nature.

[35]  Douglas D. Richman,et al.  HIV-Specific Cd8+ T Cells Produce Antiviral Cytokines but Are Impaired in Cytolytic Function , 2000, The Journal of experimental medicine.

[36]  F. Marincola,et al.  HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[37]  A. Sette,et al.  4-1BB Costimulation Is Required for Protective Anti-Viral Immunity After Peptide Vaccination1 , 2000, The Journal of Immunology.

[38]  M. Bachmann,et al.  Analysis of 4-1BB ligand (4-1BBL)-deficient mice and of mice lacking both 4-1BBL and CD28 reveals a role for 4-1BBL in skin allograft rejection and in the cytotoxic T cell response to influenza virus. , 1999, Journal of immunology.

[39]  R. Ahmed,et al.  4-1BB ligand, a member of the TNF family, is important for the generation of antiviral CD8 T cell responses. , 1999, Journal of immunology.

[40]  C. Takahashi,et al.  Cutting edge: 4-1BB is a bona fide CD8 T cell survival signal. , 1999, Journal of immunology.

[41]  L. Weinberger,et al.  Dramatic Rise in Plasma Viremia after CD8+ T Cell Depletion in Simian Immunodeficiency Virus–infected Macaques , 1999, The Journal of experimental medicine.

[42]  D. Montefiori,et al.  Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. , 1999, Science.

[43]  B. Kwon,et al.  Role of 4-1BB in immune responses. , 1998, Seminars in immunology.

[44]  T. Mak,et al.  CD28-independent, TRAF2-dependent Costimulation of Resting T Cells by 4-1BB Ligand , 1998, The Journal of experimental medicine.

[45]  M A Nowak,et al.  Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. , 1998, Science.

[46]  Young‐June Kim,et al.  Human 4‐1BB regulates CD28 co‐stimulation to promote Th1 cell responses , 1998, European journal of immunology.

[47]  S. Kim,et al.  The potential roles of 4-1BB costimulation in HIV type 1 infection. , 1998, AIDS research and human retroviruses.

[48]  A. Aruffo,et al.  4-1BB Costimulatory Signals Preferentially Induce CD8+ T Cell Proliferation and Lead to the Amplification In Vivo of Cytotoxic T Cell Responses , 1997, The Journal of experimental medicine.

[49]  Lieping Chen,et al.  Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors , 1997, Nature Medicine.

[50]  Philip J. R. Goulder,et al.  Phenotypic Analysis of Antigen-Specific T Lymphocytes , 1996, Science.

[51]  J. Bluestone,et al.  CD28/B7 system of T cell costimulation. , 1996, Annual review of immunology.

[52]  A. Perelson,et al.  Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection , 1995, Nature.

[53]  D. Ho,et al.  Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome , 1994, Journal of virology.

[54]  G. Thiele,et al.  Enzyme-linked immunosorbent assay (ELISA) for detecting antibodies in sera of patients with adenovirus infection. , 1989, Journal of virological methods.

[55]  T. Watts,et al.  TNF/TNFR family members in costimulation of T cell responses. , 2005, Annual review of immunology.

[56]  J. Borst,et al.  Lethal T cell immunodeficiency induced by chronic costimulation via CD27-CD70 interactions , 2003, Nature Immunology.

[57]  J. Altman,et al.  In vivo stimulation of CD137 broadens primary antiviral CD8+ T cell responses , 2002, Nature Immunology.