The microbial mimic poly IC induces durable and protective CD4+ T cell immunity together with a dendritic cell targeted vaccine

CD4+ Th1 type immunity is implicated in resistance to global infectious diseases. To improve the efficacy of T cell immunity induced by human immunodeficiency virus (HIV) vaccines, we are developing a protein-based approach that directly harnesses the function of dendritic cells (DCs) in intact lymphoid tissues. Vaccine proteins are selectively delivered to DCs by antibodies to DEC-205/CD205, a receptor for antigen presentation. We find that polyriboinosinic:polyribocytidylic acid (poly IC) independently serves as an adjuvant to allow a DC-targeted protein to induce protective CD4+ T cell responses at a mucosal surface, the airway. After two doses of DEC-targeted, HIV gag p24 along with poly IC, responder CD4+ T cells have qualitative features that have been correlated with protective function. The T cells simultaneously make IFN-γ, tumor necrosis factor (TNF)-α, and IL-2, and in high amounts for prolonged periods. The T cells also proliferate and continue to secrete IFN-γ in response to HIV gag p24. The adjuvant role of poly IC requires Toll-like receptor (TLR) 3 and melanoma differentiation-associated gene-5 (MDA5) receptors, but its analog poly IC12U requires only TLR3. We suggest that poly IC be tested as an adjuvant with DC-targeted vaccines to induce numerous multifunctional CD4+ Th1 cells with proliferative capacity.

[1]  B. Thiers,et al.  Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major , 2008 .

[2]  B. Pulendran,et al.  The science of adjuvants , 2007, Expert review of vaccines.

[3]  Z. Grossman,et al.  Progressive CD4+ central–memory T cell decline results in CD4+ effector–memory insufficiency and overt disease in chronic SIV infection , 2007, The Journal of experimental medicine.

[4]  T. Ichinohe,et al.  Intranasal immunization with H5N1 vaccine plus Poly I:Poly C12U, a Toll-like receptor agonist, protects mice against homologous and heterologous virus challenge. , 2007, Microbes and infection.

[5]  P. Goepfert,et al.  Human Immunodeficiency Virus Type 1 Controllers but Not Noncontrollers Maintain CD4 T Cells Coexpressing Three Cytokines , 2007, Journal of Virology.

[6]  R. Steinman,et al.  A subset of dendritic cells induces CD4+ T cells to produce IFN-γ by an IL-12–independent but CD70-dependent mechanism in vivo , 2007, The Journal of experimental medicine.

[7]  R. Flavell,et al.  TLR3 Is Essential for the Induction of Protective Immunity against Punta Toro Virus Infection by the Double-Stranded RNA (dsRNA), Poly(I:C12U), but not Poly(I:C): Differential Recognition of Synthetic dsRNA Molecules1 , 2007, The Journal of Immunology.

[8]  R. Koup,et al.  Acquisition of direct antiviral effector functions by CMV-specific CD4+ T lymphocytes with cellular maturation , 2006, The Journal of experimental medicine.

[9]  A. Tyznik,et al.  Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells , 2006, Nature.

[10]  Richard A Flavell,et al.  Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Brian R. Sloat,et al.  Nasal Immunization with Anthrax Protective Antigen Protein Adjuvanted with Polyriboinosinic–Polyribocytidylic Acid Induced Strong Mucosal and Systemic Immunities , 2006, Pharmaceutical Research.

[12]  Mario Roederer,et al.  Toll-like receptor agonists influence the magnitude and quality of memory T cell responses after prime-boost immunization in nonhuman primates , 2006, The Journal of experimental medicine.

[13]  R. Steinman,et al.  Intensified and protective CD4+ T cell immunity in mice with anti–dendritic cell HIV gag fusion antibody vaccine , 2006, The Journal of experimental medicine.

[14]  R. Steinman,et al.  Antigen targeting to dendritic cells elicits long-lived T cell help for antibody responses , 2006, The Journal of experimental medicine.

[15]  R. Koup,et al.  HIV Gag protein conjugated to a Toll-like receptor 7/8 agonist improves the magnitude and quality of Th1 and CD8+ T cell responses in nonhuman primates. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[16]  R. Steinman,et al.  Dendritic Cell-Specific Intercellular Adhesion Molecule 3-Grabbing Nonintegrin/CD209 Is Abundant on Macrophages in the Normal Human Lymph Node and Is Not Required for Dendritic Cell Stimulation of the Mixed Leukocyte Reaction1 , 2005, The Journal of Immunology.

[17]  J. Sprent,et al.  Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection , 2005, The Journal of experimental medicine.

[18]  Ross M. Kedl,et al.  Immunization with HIV-1 Gag Protein Conjugated to a TLR7/8 Agonist Results in the Generation of HIV-1 Gag-Specific Th1 and CD8+ T Cell Responses , 2005, The Journal of Immunology.

[19]  H. Agut,et al.  Combination of HIV-1-specific CD4 Th1 cell responses and IgG2 antibodies is the best predictor for persistence of long-term nonprogression. , 2005, The Journal of infectious diseases.

[20]  B. Pulendran.  Variegation of the Immune Response with Dendritic Cells and Pathogen Recognition Receptors1 , 2005, The Journal of Immunology.

[21]  R. Flavell,et al.  Toll-like receptor 3 promotes cross-priming to virus-infected cells , 2005, Nature.

[22]  N. Klimas,et al.  Results of a double-blind placebo-controlled study of the double-stranded RNA drug polyI:PolyC12U in the treatment of HIV infection , 1996, European Journal of Clinical Microbiology and Infectious Diseases.

[23]  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.

[24]  R. Koup,et al.  Correlates of immune protection in HIV-1 infection: what we know, what we don't know, what we should know , 2004, Nature Medicine.

[25]  M. Bevan.  Helping the CD8+ T-cell response , 2004, Nature Reviews Immunology.

[26]  R. Steinman,et al.  In Vivo Targeting of Antigens to Maturing Dendritic Cells via the DEC-205 Receptor Improves T Cell Vaccination , 2004, The Journal of experimental medicine.

[27]  G. Pantaleo,et al.  Skewed representation of functionally distinct populations of virus-specific CD4 T cells in HIV-1-infected subjects with progressive disease: changes after antiretroviral therapy. , 2004, Blood.

[28]  S. Kaufmann.  Novel vaccination strategies. , 2004 .

[29]  P. Borrow,et al.  Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon , 2003, Nature Immunology.

[30]  B. Bloom,et al.  The vaccine book. , 2003 .

[31]  Annapurna Vyakarnam,et al.  Presence of HIV-1 Gag-Specific IFN-γ+IL-2+ and CD28+IL-2+ CD4 T Cell Responses Is Associated with Nonprogression in HIV-1 Infection1 , 2002, The Journal of Immunology.

[32]  R. Steinman,et al.  The CD8+ Dendritic Cell Subset Selectively Endocytoses Dying Cells in Culture and In Vivo , 2002, The Journal of experimental medicine.

[33]  Michel C. Nussenzweig,et al.  Dendritic Cells Induce Peripheral T Cell Unresponsiveness under Steady State Conditions in Vivo , 2001, The Journal of experimental medicine.

[34]  B. Spellberg,et al.  Type 1/Type 2 immunity in infectious diseases. , 2001, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[35]  R. Zinkernagel,et al.  Cd4+ T Cell Subsets during Virus Infection , 2000, The Journal of experimental medicine.

[36]  R. Zinkernagel,et al.  CD4 1 T Cell Subsets during Virus Infection: Protective Capacity Depends on Effector Cytokine Secretion and on Migratory Capability , 2000 .

[37]  C Caux,et al.  Immunobiology of dendritic cells. , 2000, Annual review of immunology.

[38]  B. Pulendran,et al.  Distinct dendritic cell subsets differentially regulate the class of immune response in vivo. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[39]  R. Maldonado-López,et al.  CD8α+ and CD8α− Subclasses of Dendritic Cells Direct the Development of Distinct T Helper Cells In Vivo , 1999, The Journal of experimental medicine.

[40]  K. Shortman,et al.  Dendritic cell subtypes in mouse lymphoid organs: cross-correlation of surface markers, changes with incubation, and differences among thymus, spleen, and lymph nodes. , 1997, Journal of immunology.

[41]  R. Steinman,et al.  The receptor DEC-205 expressed by dendritic cells and thymic epithelial cells is involved in antigen processing , 1995, Nature.

[42]  C. Rinaldo,et al.  A phase I study of ampligen in human immunodeficiency virus-infected subjects. , 1992, The Journal of infectious diseases.

[43]  R. Steinman,et al.  The cell surface of mouse dendritic cells: FACS analyses of dendritic cells from different tissues including thymus. , 1989, Cellular immunology.

[44]  G. Kraal,et al.  Langerhans' cells, veiled cells, and interdigitating cells in the mouse recognized by a monoclonal antibody , 1986, The Journal of experimental medicine.

[45]  A. Freeman,et al.  Pharmacologic effects of polyinosinic• polycytidylic acid in man , 1977, Journal of medical virology.

[46]  G. P. Burke,et al.  Ssytemic effects of intravenous polyriboinosinic-polyribocytidylic acid in man. , 1976, Journal of the National Cancer Institute.

[47]  V. Devita,et al.  A phase I-II trial of multiple-dose polyriboinosic-polyribocytidylic acid in patieonts with leukemia or solid tumors. , 1976, Journal of the National Cancer Institute.