T Cell Costimulatory Molecules in Anti-Viral Immunity: Potential Role in Immunotherapeutic Vaccines

STANIER REVIEW T cell costimulatory molecules in anti-viral immunity: Potential role in immunotherapeutic vaccines Tania H Watts PhD, Edward M Bertram PhD, Jacob Bukczynski BSc, Tao Wen PhD TH Watts, EM Bertram, J Bukczynski, T Wen. T cell Les molécules costimulatoires des lymphocytes T costimulatory molecules in anti-viral immunity: Potential role dans l’immunité antivirale : Le rôle potentiel in immunotherapeutic vaccines. Can J Infect Dis 2003;14(4):221-229. des vaccins immunothérapeutiques T lymphocyte activation is required to eliminate or control intracel- L’activation des lymphocytes T est nécessaire pour éliminer ou contrôler lular viruses. The activation of T cells requires both an antigen les virus intracellulaires. Cette activation exige à la fois un signal specific signal, involving the recognition of a peptide/major histo- antigénique précis, exigeant la reconnaissance d’un multimère complexe compatibility protein complex by the T cell receptor, as well as addi- d’histocompatibilité peptide-majeur par le récepteur des lymphocytes T et tional costimulatory signals. In chronic viral diseases, T cell des signaux costimulatoires supplémentaires. En cas de maladies virales responses, although present, are unable to eliminate the infection. By chroniques, les réponses des lymphocytes T, bien qu’elles soient présentes, providing antigens and costimulatory molecules together, investiga- ne réussissent pas à éliminer l’infection. En fournissant à la fois les tors may be able to increase and broaden the immune response, result- antigènes et les molécules costimulatoires, les chercheurs pourraient ing in better immunological control or even elimination of the accroître et étendre la réponse immunitaire, ce qui assurerait un meilleur infection. Recent progress in understanding the function of contrôle immunologique ou éliminerait même l’infection. Les progrès costimulatory molecules suggests that different costimulatory mole- récents dans la compréhension de la fonction des molécules cules are involved in initial immune responses than are involved in costimulatoires laissent supposer que les molécules costimulatoires qui recall responses. These new developments have important implica- participent aux réponses immunitaires initiales diffèrent de celles utilisées tions for therapeutic vaccine design. In this review the authors dis- en cas de réponses après un rappel. Ces nouveaux développements ont des cuss the function of T cell costimulatory molecules in immune conséquences importantes pour la conception de vaccins thérapeutiques. system activation and their potential for enhancing the efficacy of Dans la présente analyse, les auteurs traitent de la fonction des therapeutic vaccines. molécules costimulatoires des lymphocytes T dans l’activation du système immunitaire et de leur potentiel pour améliorer l’efficacité des Key Words: Immunity; Therapeutic vaccines; Lymphocytes; vaccins thérapeutiques. Vaccination; Viral infection n order to develop successful vaccines against chronic viral this review, we provide some background on how T cell Idiseases it is widely thought that a cell-mediated immune immunity is initiated, the nature of the costimulatory response is required to eliminate or control intracellular molecules involved in this process, and how this knowledge viruses. For a protective immune response it is important to can be applied to therapeutic vaccines. induce long term immunological memory. The initial activation of T cells requires both an antigen specific signal, T CELLS AND IMMUNITY TO VIRUSES involving the recognition of a peptide/major histocompati- Although antibodies can be effective in neutralizing extracel- bility protein (MHC) complex by the T cell receptor as well lular viruses, CD8+ T cells are important in killing virally as additional costimulatory signals. Only when the T cell rec- infected cells and CD4+ T cells are critical in providing help ognizes both the antigen and a costimulatory signal on the for both antibody-mediated and CD8+ T cell-mediated dendritic cell (DC) (an antigen presenting cell [APC]) is an responses. The initial T cell response to pathogens is depend- immune response initiated. The idea of a therapeutic vaccine ent on the activation of APCs. Figure 1 summarizes the cur- is that the natural immune response, although present, may rent view of how this process occurs. DCs are thought to be be suboptimal. By providing antigens and costimulatory mol- the critical APCs for the initiation of T cell responses (1,2). ecules together, one may be able to provide a strong enough DCs are a diverse group of APCs scattered throughout the response to eliminate, or at least better contain, the virus. In skin and tissues. In their resting state, DCs express receptors Department of Immunology, University of Toronto, Toronto, Ontario This review is based on a lecture given at the Stanier Institute Symposium, “Vaccine preparations and vaccination through understanding pathogenesis”, held on November 22, 2002, University of British Columbia. Correspondence and reprints: Dr Tania H Watts, University of Toronto, Department of Immunology, Room 5263 Medical Sciences Building, 1 King's College Circle, Toronto, Ontario M5S 1A8. Telephone 416-978-4551, fax 416-978-1938, e-mail [email protected] Received for publication April 23, 2003. Accepted April 24, 2003 Can J Infect Dis Vol 14 No 4 July/August 2003 ©2003 Pulsus Group Inc. All rights reserved 221 Watts et al a) Pathogens TOLL LIKE RECEPTORS AND MICROBIAL RECOGNITION TLR activation migration Mycoplasmal dsRNALPS flagellin CpG ODNs lipoprotein activation b) TLR3 TLR4 TLR6 TLR5 TLR9 immature DC TLR2 at site of infection mature DC Ag/MHC Costimulatory TCR molecules c) naïve Gene expression T cell in Inflammatory response Activated draining T cell lymph node Figure 2) Toll-like receptors (TLRs) and microbial recognition. There are at least 10 TLRs and their diversity may be increased by het- effector T cells (tissues) erodimerization. A subset of TLRs and their known ligands are shown here. TLRs are pattern recognition receptors that recognize conserved Figure 1) Pathogen activation of dendritic cells and the initiation of a molecular patterns exhibited by pathogens, including bacterial cell wall T cell response. a) Immature dendritic cells in the tissues express recep- components and bacterial or viral nucleic acids. TLR9 recognizes tors for microbial uptake as well as Toll-like receptors (TLRs), pattern demethylated CpG motifs that are suppressed in mammalian DNA. recognition receptors that relay signals to the antigen presenting cell TLR9 is shown here as a surface receptor but there is evidence that the indicating that an infectious agent is present. b) After recognizing the recognition actually takes place intracellularly. Once engaged by their lig- presence of an infectious agent, dendritic cells (DCs) undergo a matu- ands, TLRs, via signaling intermediates, signal the activation of nuclear ration process, change their chemokine receptor expression and migrate factor-κB in antigen presenting cells, leading to new gene transcription to the draining lymph nodes. Mature dendritic cells upregulate major and upregulation of a program of inflammatory gene expression. histocompatibility complex (MHC) proteins as well as costimulatory dsRNA Double-stranded ribonucleic acid; LPS Lipopolysaccharide; molecules important for the activation of naïve T cells. c) Following ODN Oligodinucleotide. Adapted from (72) activation and clonal expansion in the lymphoid tissues, activated effector T cells home to the site of infection and exert their effector functions (cytokine secretion, killing). Ag Antigen; TCR T cell receptor triggering inflammation and immunity. This activation process renders DCs competent to activate naïve T cells in the lymphoid organs. Naive T cells, via their clonally distributed anti- suitable for pathogen uptake, as well as receptors capable of gen-specific T cell receptors, recognize peptide-MHC sensing infection. Once activated by exposure to pathogens or complexes presented on the activated DCs. At the same time, inflammatory stimuli, DCs undergo a maturation process that T cells need to recognize so-called ‘costimulatory molecules’ in involves their migration to the draining lymph node and order to be activated. Antigen presentation in the lymphoid increased cell surface expression of molecules involved in T organs results in clonal expansion leading to a population of cell activation. activated ‘effector’ T cells (Figure 1). These effector T cells DCs and other APCs express a family of receptors known as then home back to the site of infection, where they carry out the Toll-like receptors (TLRs) (3). These receptors are pattern their functions in eliminating or containing the infection. The recognition receptors that bind conserved features of pathogens. finding that the initiation of the T cell response requires the There are at least 10 such receptors and their diversity is presence of costimulatory molecules induced by microbial infec- increased by heterodimerization (Figure 2). For example, tion explains in part how the immune system can respond vigor- TLR4 is required for the response to bacterial lipopolysaccha- ously to an infection while avoiding recognition of self-tissues. ride. TLR3 recognizes double stranded ribonucleic acid (dsRNA) associated with viral infections and TLR9 recognizes WHAT IS A T CELL COSTIMULATORY demethylated CpG motifs that are enriched in bacterial DNA. MOLECULE? Once triggered by these

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