ABSTRACT
One of the current challenges in vaccine design is the development of antigen delivery systems or vaccination strategies that induce high protective levels of CD8+ T cells. These cells are crucial for protection against certain tumours and intracellular pathogens such as the liver-stage parasite of malaria. A liver-stage malaria vaccine should therefore include CD8+ T-cell-inducing components. This review provides an overview of prime-boost immunisation strategies that result in protective CD8+ T-cell responses against malaria with an emphasis on work from our laboratory. Possible mechanisms explaining why heterologous prime-boost strategies, in particular boosting with replication-impaired recombinant poxviruses, are so effective are discussed.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Immunization, Secondary/methods , Adjuvants, Immunologic/administration & dosage , Animals , Epitopes/administration & dosage , Genetic Vectors , Humans , Malaria/immunology , Malaria/prevention & control , Malaria Vaccines/administration & dosage , Mice , Primates , Vaccines, DNA/administration & dosageABSTRACT
The protection of cells expressing class I HLA molecules from NK lysis is mediated by natural killer cell inhibitory receptors (NKIR). Using site-directed mutagenesis, residues on HLA-C that determine the locus specificity (alphaVal-76), allotype group specificity (a dimorphism alphaAsn-80/Lys-80), and affinity of NKIR binding (a second pair of dimorphisms, alphaAla-73, Asp-90 or alphaThr-73, Ala-90) have been identified. Thus the "footprint" of the NKIR on the alpha1 helix of the class I MHC molecule HLA-C and its associated beta strands are similar in position to the site occupied by superantigens on and behind the alpha1 helix of the class II MHC molecule HLA-DR1, but further toward its C-terminus. The intermediate affinity binding of NKIR to HLA-C, determined by alpha73 and alpha90, has an essential role in preventing cross-reactivity and ensuring the availability of NK cells for immunosurveillance; low affinity and high affinity mutants are both physiologically impaired.
Subject(s)
HLA-C Antigens/metabolism , Killer Cells, Natural/immunology , Receptors, Immunologic/genetics , Receptors, Immunologic/immunology , Adult , Amino Acid Sequence , Binding Sites/genetics , Binding Sites/immunology , Binding, Competitive/immunology , Cell Line , HLA-C Antigens/chemistry , HLA-C Antigens/genetics , Humans , Molecular Sequence Data , Mutagenesis, Site-Directed/genetics , Receptors, Immunologic/analysis , Receptors, KIRABSTRACT
The expression, or lack thereof, of class I MHC glycoproteins has a marked influence on natural killer cell function. Cells which do not express class I MHC molecules are susceptible to lysis by NK cells, and transfection of these targets with class I MHC genes can render these cells resistant to NK attack. This inhibition of NK-killing is mediated by a novel family of receptors expressed mainly on NK cells, but also found on some T-cells. The function of these class I MHC binding receptors when expressed on T-cells is discussed also and a novel co-stimulatory activity of NKAR described. Lastly, a novel mechanism by which human cytomegalovirus evades immune surveillance by NK cells is documented.
Subject(s)
Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Receptors, Immunologic/physiology , Humans , LigandsABSTRACT
An important feature of the human immune system is the ability of T cells to respond to small quantities of antigen. Class II major histocompatibility complex (MHC)-restricted T cells that expressed a costimulatory natural killer (NK) cell receptor for class I MHC proteins were cloned. In the presence of low doses of superantigen, the proliferative response of these T cell clones was three- to ninefold greater when the T cells were costimulated by way of the NK receptor. Thus, the action of costimulatory NK receptors on T cells may play a significant role in initiating and sustaining immune responses.
