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Cell-Mediated Immune Effector Functions in Chickens
Cell-Mediated Immune Effector Functions in Chickens KAREL A. SCHAT Department of Avian and Aquatic Animal Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853
1994 Poultry Science 73:1077-1081
INTRODUCTION
Cell-mediated immune (CMI) responses are important for the protection of animals against intracellular pathogens. Over the last decade, important progress has been made in the characterization of effector cells, in vitro cultivation of effector cells, and especially the processing of antigens in the context of Class I and Class II MHC antigens. Unfortunately, most of this progress has been made in mammalian species and not in chickens. Although it can be expected that the immune responses in birds are similar to those in mammalian species, the application of these general concepts to specific questions concerning immunity and health in chickens is lacking. In general, there is a paucity of data on antiviral CMI responses in chickens with the exception of Marek's disease virus (MDV) and reticuloendotheliosis virus (REV) infections. Although Marek's disease (MD) is often used as an example of antitumor immunity, there is little or no
Received for publication July 25, 1993. Accepted for publication February 8, 1994.
direct evidence that immune responses against tumor cells are indeed directed against neoantigens or modified cellular antigens and not against viral antigens (Schat, 1992). Recent reviews have dealt extensively with the immune responses against these two viral infections (Schat, 1991a, 1992; Sharma et al, 1991) and parasitic and bacterial infections (Lillehoj, 1991). In this paper, salient points on recent developments in the understanding of the immune responses to viral infections in general will be related to questions concerning the development of CMI against viral diseases in chickens. MAJOR HISTOCOMPATIBILITY COMPLEX
The MHC complex plays a central role in the presentation of antigens by antigenpresenting cells to helper T cells and cytotoxic T lymphocytes (CTL). Moreover, CTL can only kill virus-infected target cells or tumor cells when viral or tumor antigens are presented in association with the same Class I MHC antigens of the effector cells. Moreover, natural killer (NK) cells may only be able to lyse target
1077
Downloaded from http://ps.oxfordjournals.org/ at Simon Fraser University on May 30, 2015
ABSTRACT Cell-mediated immune responses form an important part of the protection against intracellular pathogens. The MHC Class I and Class II antigens are important for the proper presentation of degraded proteins to cytotoxic T lymphocytes (CTL) and helper T cells, respectively. Recent developments in the knowledge of the molecular structure of the MHC in relation to antigen presentation are discussed. Although CTL are important, there is a paucity of information concerning their relevance for the control of viral diseases in poultry. A newly developed approach of stable transfection of viral genes into cell lines transformed by reticuloendotheliosis virus has shown promise as a method to define proteins, which are important for the induction of cell-mediated immunity. (Key words: cytotoxic T cells, major histocompatibility complex, cell-mediated immunity, antigen presentation, antiviral immunity)
1078
SCHAT
EFFECTOR CELLS In addition to neutralizing antibodies, CMI responses are important for the protection against and recovery from virus infections. A number of different cellular mechanisms are involved in CMI responses. Cytotoxic T lymphocytes (Schat, 1991b) and cells mediating antibody-dependent, cell-mediated cytotoxicity (ADCC) develop as part of an antigen-specific immune response as a consequence of natural infection or vaccination. In contrast, NK cells and macrophages form an important part of the natural defense against infection and tumor cells in naive individuals. This section will be limited to CTL. There is little information available on the importance of ADCC in the control of diseases in chickens (Sharma and Schat, 1991). The role of macrophages and NK cells in antiviral and antitumor immunity has been discussed elsewhere (Dietert et al, 1991; Sharma and Schat, 1991; Qureshi, 1994). Cytotoxic T Lymphocytes The CD8+ CTL recognize virus-infected cells when viral antigens (see below) are presented in the context of Class I MHC antigens. However, CD4+ CTL have been described as important in the case of herpes simplex virus (Yasukawa and Zarling, 1984) and influenza virus infections (Morrison et al, 1988). Assays for either type of CTL are often performed after in vitro expansion of these cells using secondary antigen stimulation combined with interleukins. There are very few reports on functional assays demonstrating virus-specific CTL in chickens. Maccubbin and Schierman (1986) first described the presence of virusspecific, syngeneically restricted CTL in spleens of REV-infected chickens using REV-transformed cells as target cells. Weinstock et al. (1989) and Lillehoj et al. (1988) confirmed the presence of virus-specific, MHC-restricted CTL and demonstrated that these CTL expressed both Class II MHC antigens and CD8. Recently, Merkle et al. (1992) reported that REV-specific CTL are T cell receptor (TCR) 2-positive cells using spleen cells that were negatively selected for either TCR1 or TCR2. Unfor-
Downloaded from http://ps.oxfordjournals.org/ at Simon Fraser University on May 30, 2015
cells that fail to express or express different Class I MHC antigens (Versteeg, 1992; Neefjes and Momburg, 1993; Reiter, 1993). As a consequence, a thorough understanding of the structure of the MHC complex has become essential to increase our knowledge of avian immunity and especially the presentation of antigens (see below). Recent advances in the understanding of the chicken MHC locus have been reviewed by Kaufman et al. (1991) and Plachy et al. (1992). The MHC complex of the chicken contains at least three groups of cell membrane antigens, two of which are relevant to this review: the B-F and the B-L locus corresponding to the Class I and Class II genes, respectively. For some MHC haplotypes, the genes for both Class I and II MHC antigens have been cloned. Thus far, five B-L 0 and six BF genes have been identified. Recently, Kaufman et al. (1992) reported the sequences of genes for the B-F locus and j32microglobulin chain, and Zoorob et al. (1993) sequenced five different B-L /3 genes. In addition, preliminary sequence analysis of selected B-F genes has shown differences in the potential antigen binding sites for nonapeptides (Hunt and Sturgeon, 1993). Similarly, Pharr et al. (1993) reported polymorphisms in the variable regions of the B-L 0 (Class II) chain at the putative binding sites for peptides presented to helper T cells. Additional sequence information for both Class I and Class II haplotypes will be needed to further elucidate the importance of this complex for disease resistance in chickens. Recently, Briles et al. (1993) described an additional polymorphic complex, which seems to be related to the B-F and B-L complex of the MHC. This complex was designated as Rfp-Y. Thus far, three haplotypes have been identified. Genes representing two of the haplotypes crosshybridize with B-L fragments, and the third one hybridized with a B-F fragment. Briles et al. (1993) cited unpublished studies suggesting that additional haplotypes of the Rfr-Y system exist. The importance of this finding for the understanding of disease resistance or antigen presentation to either CTL or helper T cells has not yet been established.
SYMPOSIUM: CURRENT ADVANCES IN AVIAN IMMUNOLOGY
tunately, there are no reports demonstrating the induction of virus-specific CTL able to lyse target cells with the exception of the use of transfected REV cell lines. ANTIGEN PRESENTATION
present in the antigen. This in turn may help in selecting potential gene sequences that can be included in a "string-of-beads" vectored vaccine (Whitton et al, 1993). As a consequence, it may become important for the primary breeders to provide detailed information on the haplotypes present in their population of chickens. RECENT DEVELOPMENTS A new approach for the study of avian CMI response was developed by Pratt and co-workers (1992). They used MHCdefined REV-transformed cell lines, which can be lysed by MHC Class I-restricted CTL. These cells could express Marek's disease virus (MDV) genes following stable transfection. Cells were transfected by electroporation using a selection plasmid containing the neo gene (Schat et al, 1992). The cells transfected with MDV DNA fragments expressing the phosphoprotein pp38 were lysed by CTL obtained from SB-1 vaccinated chickens. The use of REVspecific CTL allowed the use of an internal control for syngeneic lysis (Pratt et al, 1992). Recently, Uni et al (1994) reported that pp38-expressing cells can also be lysed by CTL generated after infection with HVT and oncogenic, Serotype I strains of MDV. Moreover, they demonstrated that this lysis was MHC Class Irestricted using transfected target cells with different MHC alleles. Additional studies using other MDV genes are in progress in the laboratory of the author. FUTURE NEEDS Optimal production of high quality poultry products for human consumption depends to a large degree on disease control. A more detailed understanding of the immunological bases to various control procedures is paramount in this respect. In order to design more efficient vectored vaccines, it will be important to have a better understanding of the epitopes recognized by CD4+ and CD8+ cells. This will allow the incorporation of several relevant epitopes of one or more pathogens to be included in a "string-ofbeads" vaccine, as has been demonstrated for a vectored vaccine against lymphocytic
Downloaded from http://ps.oxfordjournals.org/ at Simon Fraser University on May 30, 2015
The induction of antigen-specific immune responses depends on the correct presentation of antigens to CTL or helper T cells. It has become clear over the last few years that the processing of these antigens is a complex process (for details see: Neefjes and Momburg, 1993; Takahashi, 1993). Antigens presented to CD8+ CTL are, in general, endogenously synthesized peptides, such as de novo synthesized viral proteins, which are degraded to small (often nona-) peptides by large adenosine triphosphate-dependent proteasomes. These small peptides are transported by transporter proteins to the lumen of the endoplasmic reticulum, where they bind to the antigen groove formed by assembly of the MHC Class I chain and the ^-microglobulin. This complex is then transported to the surface of the cell, where it is expressed. The binding of the antigen into the groove, which is formed by two a-helices and a 0-sheet of the MHC-chain, has been resolved for some MHC-nonapeptide combinations at the level of the atomic structure of the nonapeptide and the MHC Class I complex (Silver et al, 1992). Substitution of one or two key amino acids in the nonapeptide or in the amino acid binding pockets of the MHC molecule can determine whether the antigen will be presented to the CTL. In the case of stimulation of T helper cells, exogenously synthesized proteins enter the antigenpresenting cell by endocytosis and are degraded in the endosome to short peptides of about nine amino acids. These peptides become associated with the a-/3 chain complex of the MHC Class II antigen and are transported to the cell surface. These pathways for antigen processing have important consequences for the development of new vaccines. Knowledge about the antigen-binding pockets of the MHC Class I and II complexes will determine which amino acids need to be
1079
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SCHAT
choriomeningitis virus in mice (Whitton et al., 1993). Detailed knowledge of the antigen-binding sites in the MHC Class I and Class II molecules of the different B-F and B-L alleles present in commercial poultry will facilitate the development of such vaccines. In addition, recombinant avian interleukins are urgently needed for in vitro stimulation and propagation of CTL, which in turn would facilitate the identification of relevant nonapeptides for CMI responses.
Briles, W. E., R. M. Goto, C. Auffray, and M. M. Miller, 1993. A polymorphic system related to but genetically independent of the chicken major histocompatibility complex. Immunogenetics 37:408-411. Dietert, R. R., K. A. Golemboski, S. E. Bloom, and M. A. Qureshi, 1991. The avian macrophage in cellular immunity. Pages 71-96 in: Avian Cellular Immunology. J. M. Sharma, ed. CRC Press, Boca Raton, FL. Hunt, H. D., and M. M. Sturgeon, 1993. Evidence for the expression of multiple class I loci in chickens. Poultry Sci. 72:(Suppl. l)102.(Abstr.) Kaufman, J., R. Andersen, D. Avila, J. Engberg, J. Lambris, J. Salomonsen, K. Welmder, and K. Skjodt, 1992. Different features of the MHC class I heterodimer have evolved at different rates. Chicken B-F and Beta2-Microglobulin sequences reveal invariant surface residues. J. Immunol. 148:1532-1546. Kaufman, J., K. Skjodt, and J. Salomonsen, 1991. The B-G multigene family of the chicken major histocompatibility complex. Crit. Rev. Immunol. 11:113-143. Lillehoj, H. S., 1991. Cell-mediated immunity in parasitic and bacterial diseases. Pages 155-190 in: Avian Cellular Immunology. J. M. Sharma, ed. CRC Press, Boca Raton, FL. Lillehoj, H. S., E. P. Lillehoj, D. Weinstock, K. A. Schat, 1988. Functional and biochemical characterization of avian T lymphocyte antigens identified by monoclonal antibodies. Eur. J. Immunol. 18:2059-2065. Maccubbin, D. L., and L. W. Schierman, 1986. MHCrestricted cytotoxic response of chicken T cells: Expression, augmentation, and clonal characterization. J. Immunol. 13:12-16. Merkle, H., J. Cihak, and U. Losch, 1992. The cytotoxic T lymphocyte response in reticuloendotheliosis virus-infected chickens is mediated by alpha/beta and not gamma/delta T cells. Immunobiology 186:292-303. Morrison, L. A., V. L. Braciale, and T. J. Braciale, 1988. Antigen form influences induction and frequency of influenza-specific class I and class II MHC-restricted cytolytic T lymphocytes. J. Immunol. 141:363-368.
Downloaded from http://ps.oxfordjournals.org/ at Simon Fraser University on May 30, 2015
REFERENCES
Neefjes, J. J., and F. Momburg, 1993. Cell biology of antigen presentation. Curr. Opin. Immunol. 5: 27-34. Pharr, G. T., H. D. Hunt, L. D. Bacon, and J. B. Dodgson, 1993. Identification of class II major histocompatibility complex polymorphisms predicted to be important in peptide presentation. Poultry Sci. 72:1312-1317. Plachy, J., J.R.L. Pink, and K. Hala, 1992. Biology of the chicken MHC (B complex). Crit. Rev. Immunol. 12:47-79. Pratt, W. D., R. Morgan, and K. A. Schat, 1992. Cellmediated cytolysis of lymphoblastoid cells expressing Marek's disease virus-specific phosphorylated polypeptides. Vet. Microbiol. 33: 93-99. Qureshi, M. A., J. A. Marsh, R. R. Dietert, Y.-J. Sung, C. Nicholas-Bolnet, and J. N. Petitte, 1994. Profiles of chicken macrophage effector functions. Poultry Sci. 73:1027-1034. Reiter, Z., 1993. Dual effects of cytokines in regulation of MHC-unrestricted cell mediated cytotoxicity. Crit. Rev. Immunol. 13:1-34. Schat, K. A, 1991a. Importance of cell-mediated immunity in Marek's disease and other viral tumor diseases. Poultry Sci. 70:1165-1175. Schat, K. A , 1991b. T-cell immunity: mechanisms and soluble mediators. Pages 36-50 in: Avian Cellular Immunology. J. M. Sharma, ed. CRC Press, Boca Raton, FL. Schat, K. A., 1992. Immune responses against Marek's disease virus. Pages 233-238 in: Proceedings of the XIX World's Poultry Congress. Amsterdam, The Netherlands. Schat, K. A, W. D. Pratt, R. Morgan, D. Weinstock, and B. W. Calnek, 1992. Stable transfection of reticuloendotheliosis virus-transformed lymphoblastoid cell lines. Avian Dis. 36:432-439. Sharma, J. M., S. J. Prowse, and J. J. York, 1991. role of cellular immunity in neoplastic and nonneoplastic viral diseases. Pages 139-154 in: Avian Cellular Immunology, J. M. Sharma, ed. CRC Press, Boca Raton, FL. Sharma, J. M., and K. A. Schat, 1991. Natural immune functions. Pages 51-70 in: Avian Cellular Immunology. J. M. Sharma, ed. CRC Press, Boca Raton, FL. Silver, M. L., H.-C. Guo, J. L. Strominger, and D. C. Wiley, 1992. Atomic structure of a human MHC molecule presenting an influenza virus peptide. Nature 360:367-369. Takahshi, H., 1993. Antigen processing and presentation. Microbiol. Immunol. 37:1-9. Uni, Z., W. D. Pratt, M. M. Miller, P. H. O'Connell, and K. A. Schat, 1994. Syngeneic lysis of reticuloendotheliosis virus-transformed cell lines transfected with Marek's disease virus genes by virus-specific cytotoxic T cells. Vet. Immunol. Immunopathol. (in press). Versteeg, R., 1992. NK cells and T cells: mirror images? Immunol. Today 13:244-247. Weinstock, D., K. A. Schat, and B. W. Calnek, 1989. Cytotoxic T lymphocytes in reticuloendotheliosis virus-infected chickens. Eur. J. Immunol. 19: 267-272. Whitton, J. L., N. Sheng, M.B.A. Oldstone, and T. A. McKee, 1993. A "string-of-beads" vaccine, comprising linked minigenes, confers protection from lethal-dose virus challenge. J. Virol. 67: 348-352.
SYMPOSIUM: CURRENT ADVANCES IN AVIAN IMMUNOLOGY Yasukawa, M., and J. M. Zarling, 1984. Human cytotoxic T cell clones directed against herpes simplex virus-infected cells. I. Lysis restricted by HLC class II MB and DR antigens. J. Immunol. 133:422-427.
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Zoorob, R., A. Bernot, D. M. Renoir, F. Choukri, and C. Auffray, 1993. Chicken major histocomparibility complex class II B genes: analysis of interallelic and interlocus sequence variance. Eur. J. Immunol. 23:1139-1145.
Downloaded from http://ps.oxfordjournals.org/ at Simon Fraser University on May 30, 2015
1994 Poultry Science 73:1077-1081
INTRODUCTION
Cell-mediated immune (CMI) responses are important for the protection of animals against intracellular pathogens. Over the last decade, important progress has been made in the characterization of effector cells, in vitro cultivation of effector cells, and especially the processing of antigens in the context of Class I and Class II MHC antigens. Unfortunately, most of this progress has been made in mammalian species and not in chickens. Although it can be expected that the immune responses in birds are similar to those in mammalian species, the application of these general concepts to specific questions concerning immunity and health in chickens is lacking. In general, there is a paucity of data on antiviral CMI responses in chickens with the exception of Marek's disease virus (MDV) and reticuloendotheliosis virus (REV) infections. Although Marek's disease (MD) is often used as an example of antitumor immunity, there is little or no
Received for publication July 25, 1993. Accepted for publication February 8, 1994.
direct evidence that immune responses against tumor cells are indeed directed against neoantigens or modified cellular antigens and not against viral antigens (Schat, 1992). Recent reviews have dealt extensively with the immune responses against these two viral infections (Schat, 1991a, 1992; Sharma et al, 1991) and parasitic and bacterial infections (Lillehoj, 1991). In this paper, salient points on recent developments in the understanding of the immune responses to viral infections in general will be related to questions concerning the development of CMI against viral diseases in chickens. MAJOR HISTOCOMPATIBILITY COMPLEX
The MHC complex plays a central role in the presentation of antigens by antigenpresenting cells to helper T cells and cytotoxic T lymphocytes (CTL). Moreover, CTL can only kill virus-infected target cells or tumor cells when viral or tumor antigens are presented in association with the same Class I MHC antigens of the effector cells. Moreover, natural killer (NK) cells may only be able to lyse target
1077
Downloaded from http://ps.oxfordjournals.org/ at Simon Fraser University on May 30, 2015
ABSTRACT Cell-mediated immune responses form an important part of the protection against intracellular pathogens. The MHC Class I and Class II antigens are important for the proper presentation of degraded proteins to cytotoxic T lymphocytes (CTL) and helper T cells, respectively. Recent developments in the knowledge of the molecular structure of the MHC in relation to antigen presentation are discussed. Although CTL are important, there is a paucity of information concerning their relevance for the control of viral diseases in poultry. A newly developed approach of stable transfection of viral genes into cell lines transformed by reticuloendotheliosis virus has shown promise as a method to define proteins, which are important for the induction of cell-mediated immunity. (Key words: cytotoxic T cells, major histocompatibility complex, cell-mediated immunity, antigen presentation, antiviral immunity)
1078
SCHAT
EFFECTOR CELLS In addition to neutralizing antibodies, CMI responses are important for the protection against and recovery from virus infections. A number of different cellular mechanisms are involved in CMI responses. Cytotoxic T lymphocytes (Schat, 1991b) and cells mediating antibody-dependent, cell-mediated cytotoxicity (ADCC) develop as part of an antigen-specific immune response as a consequence of natural infection or vaccination. In contrast, NK cells and macrophages form an important part of the natural defense against infection and tumor cells in naive individuals. This section will be limited to CTL. There is little information available on the importance of ADCC in the control of diseases in chickens (Sharma and Schat, 1991). The role of macrophages and NK cells in antiviral and antitumor immunity has been discussed elsewhere (Dietert et al, 1991; Sharma and Schat, 1991; Qureshi, 1994). Cytotoxic T Lymphocytes The CD8+ CTL recognize virus-infected cells when viral antigens (see below) are presented in the context of Class I MHC antigens. However, CD4+ CTL have been described as important in the case of herpes simplex virus (Yasukawa and Zarling, 1984) and influenza virus infections (Morrison et al, 1988). Assays for either type of CTL are often performed after in vitro expansion of these cells using secondary antigen stimulation combined with interleukins. There are very few reports on functional assays demonstrating virus-specific CTL in chickens. Maccubbin and Schierman (1986) first described the presence of virusspecific, syngeneically restricted CTL in spleens of REV-infected chickens using REV-transformed cells as target cells. Weinstock et al. (1989) and Lillehoj et al. (1988) confirmed the presence of virus-specific, MHC-restricted CTL and demonstrated that these CTL expressed both Class II MHC antigens and CD8. Recently, Merkle et al. (1992) reported that REV-specific CTL are T cell receptor (TCR) 2-positive cells using spleen cells that were negatively selected for either TCR1 or TCR2. Unfor-
Downloaded from http://ps.oxfordjournals.org/ at Simon Fraser University on May 30, 2015
cells that fail to express or express different Class I MHC antigens (Versteeg, 1992; Neefjes and Momburg, 1993; Reiter, 1993). As a consequence, a thorough understanding of the structure of the MHC complex has become essential to increase our knowledge of avian immunity and especially the presentation of antigens (see below). Recent advances in the understanding of the chicken MHC locus have been reviewed by Kaufman et al. (1991) and Plachy et al. (1992). The MHC complex of the chicken contains at least three groups of cell membrane antigens, two of which are relevant to this review: the B-F and the B-L locus corresponding to the Class I and Class II genes, respectively. For some MHC haplotypes, the genes for both Class I and II MHC antigens have been cloned. Thus far, five B-L 0 and six BF genes have been identified. Recently, Kaufman et al. (1992) reported the sequences of genes for the B-F locus and j32microglobulin chain, and Zoorob et al. (1993) sequenced five different B-L /3 genes. In addition, preliminary sequence analysis of selected B-F genes has shown differences in the potential antigen binding sites for nonapeptides (Hunt and Sturgeon, 1993). Similarly, Pharr et al. (1993) reported polymorphisms in the variable regions of the B-L 0 (Class II) chain at the putative binding sites for peptides presented to helper T cells. Additional sequence information for both Class I and Class II haplotypes will be needed to further elucidate the importance of this complex for disease resistance in chickens. Recently, Briles et al. (1993) described an additional polymorphic complex, which seems to be related to the B-F and B-L complex of the MHC. This complex was designated as Rfp-Y. Thus far, three haplotypes have been identified. Genes representing two of the haplotypes crosshybridize with B-L fragments, and the third one hybridized with a B-F fragment. Briles et al. (1993) cited unpublished studies suggesting that additional haplotypes of the Rfr-Y system exist. The importance of this finding for the understanding of disease resistance or antigen presentation to either CTL or helper T cells has not yet been established.
SYMPOSIUM: CURRENT ADVANCES IN AVIAN IMMUNOLOGY
tunately, there are no reports demonstrating the induction of virus-specific CTL able to lyse target cells with the exception of the use of transfected REV cell lines. ANTIGEN PRESENTATION
present in the antigen. This in turn may help in selecting potential gene sequences that can be included in a "string-of-beads" vectored vaccine (Whitton et al, 1993). As a consequence, it may become important for the primary breeders to provide detailed information on the haplotypes present in their population of chickens. RECENT DEVELOPMENTS A new approach for the study of avian CMI response was developed by Pratt and co-workers (1992). They used MHCdefined REV-transformed cell lines, which can be lysed by MHC Class I-restricted CTL. These cells could express Marek's disease virus (MDV) genes following stable transfection. Cells were transfected by electroporation using a selection plasmid containing the neo gene (Schat et al, 1992). The cells transfected with MDV DNA fragments expressing the phosphoprotein pp38 were lysed by CTL obtained from SB-1 vaccinated chickens. The use of REVspecific CTL allowed the use of an internal control for syngeneic lysis (Pratt et al, 1992). Recently, Uni et al (1994) reported that pp38-expressing cells can also be lysed by CTL generated after infection with HVT and oncogenic, Serotype I strains of MDV. Moreover, they demonstrated that this lysis was MHC Class Irestricted using transfected target cells with different MHC alleles. Additional studies using other MDV genes are in progress in the laboratory of the author. FUTURE NEEDS Optimal production of high quality poultry products for human consumption depends to a large degree on disease control. A more detailed understanding of the immunological bases to various control procedures is paramount in this respect. In order to design more efficient vectored vaccines, it will be important to have a better understanding of the epitopes recognized by CD4+ and CD8+ cells. This will allow the incorporation of several relevant epitopes of one or more pathogens to be included in a "string-ofbeads" vaccine, as has been demonstrated for a vectored vaccine against lymphocytic
Downloaded from http://ps.oxfordjournals.org/ at Simon Fraser University on May 30, 2015
The induction of antigen-specific immune responses depends on the correct presentation of antigens to CTL or helper T cells. It has become clear over the last few years that the processing of these antigens is a complex process (for details see: Neefjes and Momburg, 1993; Takahashi, 1993). Antigens presented to CD8+ CTL are, in general, endogenously synthesized peptides, such as de novo synthesized viral proteins, which are degraded to small (often nona-) peptides by large adenosine triphosphate-dependent proteasomes. These small peptides are transported by transporter proteins to the lumen of the endoplasmic reticulum, where they bind to the antigen groove formed by assembly of the MHC Class I chain and the ^-microglobulin. This complex is then transported to the surface of the cell, where it is expressed. The binding of the antigen into the groove, which is formed by two a-helices and a 0-sheet of the MHC-chain, has been resolved for some MHC-nonapeptide combinations at the level of the atomic structure of the nonapeptide and the MHC Class I complex (Silver et al, 1992). Substitution of one or two key amino acids in the nonapeptide or in the amino acid binding pockets of the MHC molecule can determine whether the antigen will be presented to the CTL. In the case of stimulation of T helper cells, exogenously synthesized proteins enter the antigenpresenting cell by endocytosis and are degraded in the endosome to short peptides of about nine amino acids. These peptides become associated with the a-/3 chain complex of the MHC Class II antigen and are transported to the cell surface. These pathways for antigen processing have important consequences for the development of new vaccines. Knowledge about the antigen-binding pockets of the MHC Class I and II complexes will determine which amino acids need to be
1079
1080
SCHAT
choriomeningitis virus in mice (Whitton et al., 1993). Detailed knowledge of the antigen-binding sites in the MHC Class I and Class II molecules of the different B-F and B-L alleles present in commercial poultry will facilitate the development of such vaccines. In addition, recombinant avian interleukins are urgently needed for in vitro stimulation and propagation of CTL, which in turn would facilitate the identification of relevant nonapeptides for CMI responses.
Briles, W. E., R. M. Goto, C. Auffray, and M. M. Miller, 1993. A polymorphic system related to but genetically independent of the chicken major histocompatibility complex. Immunogenetics 37:408-411. Dietert, R. R., K. A. Golemboski, S. E. Bloom, and M. A. Qureshi, 1991. The avian macrophage in cellular immunity. Pages 71-96 in: Avian Cellular Immunology. J. M. Sharma, ed. CRC Press, Boca Raton, FL. Hunt, H. D., and M. M. Sturgeon, 1993. Evidence for the expression of multiple class I loci in chickens. Poultry Sci. 72:(Suppl. l)102.(Abstr.) Kaufman, J., R. Andersen, D. Avila, J. Engberg, J. Lambris, J. Salomonsen, K. Welmder, and K. Skjodt, 1992. Different features of the MHC class I heterodimer have evolved at different rates. Chicken B-F and Beta2-Microglobulin sequences reveal invariant surface residues. J. Immunol. 148:1532-1546. Kaufman, J., K. Skjodt, and J. Salomonsen, 1991. The B-G multigene family of the chicken major histocompatibility complex. Crit. Rev. Immunol. 11:113-143. Lillehoj, H. S., 1991. Cell-mediated immunity in parasitic and bacterial diseases. Pages 155-190 in: Avian Cellular Immunology. J. M. Sharma, ed. CRC Press, Boca Raton, FL. Lillehoj, H. S., E. P. Lillehoj, D. Weinstock, K. A. Schat, 1988. Functional and biochemical characterization of avian T lymphocyte antigens identified by monoclonal antibodies. Eur. J. Immunol. 18:2059-2065. Maccubbin, D. L., and L. W. Schierman, 1986. MHCrestricted cytotoxic response of chicken T cells: Expression, augmentation, and clonal characterization. J. Immunol. 13:12-16. Merkle, H., J. Cihak, and U. Losch, 1992. The cytotoxic T lymphocyte response in reticuloendotheliosis virus-infected chickens is mediated by alpha/beta and not gamma/delta T cells. Immunobiology 186:292-303. Morrison, L. A., V. L. Braciale, and T. J. Braciale, 1988. Antigen form influences induction and frequency of influenza-specific class I and class II MHC-restricted cytolytic T lymphocytes. J. Immunol. 141:363-368.
Downloaded from http://ps.oxfordjournals.org/ at Simon Fraser University on May 30, 2015
REFERENCES
Neefjes, J. J., and F. Momburg, 1993. Cell biology of antigen presentation. Curr. Opin. Immunol. 5: 27-34. Pharr, G. T., H. D. Hunt, L. D. Bacon, and J. B. Dodgson, 1993. Identification of class II major histocompatibility complex polymorphisms predicted to be important in peptide presentation. Poultry Sci. 72:1312-1317. Plachy, J., J.R.L. Pink, and K. Hala, 1992. Biology of the chicken MHC (B complex). Crit. Rev. Immunol. 12:47-79. Pratt, W. D., R. Morgan, and K. A. Schat, 1992. Cellmediated cytolysis of lymphoblastoid cells expressing Marek's disease virus-specific phosphorylated polypeptides. Vet. Microbiol. 33: 93-99. Qureshi, M. A., J. A. Marsh, R. R. Dietert, Y.-J. Sung, C. Nicholas-Bolnet, and J. N. Petitte, 1994. Profiles of chicken macrophage effector functions. Poultry Sci. 73:1027-1034. Reiter, Z., 1993. Dual effects of cytokines in regulation of MHC-unrestricted cell mediated cytotoxicity. Crit. Rev. Immunol. 13:1-34. Schat, K. A, 1991a. Importance of cell-mediated immunity in Marek's disease and other viral tumor diseases. Poultry Sci. 70:1165-1175. Schat, K. A , 1991b. T-cell immunity: mechanisms and soluble mediators. Pages 36-50 in: Avian Cellular Immunology. J. M. Sharma, ed. CRC Press, Boca Raton, FL. Schat, K. A., 1992. Immune responses against Marek's disease virus. Pages 233-238 in: Proceedings of the XIX World's Poultry Congress. Amsterdam, The Netherlands. Schat, K. A, W. D. Pratt, R. Morgan, D. Weinstock, and B. W. Calnek, 1992. Stable transfection of reticuloendotheliosis virus-transformed lymphoblastoid cell lines. Avian Dis. 36:432-439. Sharma, J. M., S. J. Prowse, and J. J. York, 1991. role of cellular immunity in neoplastic and nonneoplastic viral diseases. Pages 139-154 in: Avian Cellular Immunology, J. M. Sharma, ed. CRC Press, Boca Raton, FL. Sharma, J. M., and K. A. Schat, 1991. Natural immune functions. Pages 51-70 in: Avian Cellular Immunology. J. M. Sharma, ed. CRC Press, Boca Raton, FL. Silver, M. L., H.-C. Guo, J. L. Strominger, and D. C. Wiley, 1992. Atomic structure of a human MHC molecule presenting an influenza virus peptide. Nature 360:367-369. Takahshi, H., 1993. Antigen processing and presentation. Microbiol. Immunol. 37:1-9. Uni, Z., W. D. Pratt, M. M. Miller, P. H. O'Connell, and K. A. Schat, 1994. Syngeneic lysis of reticuloendotheliosis virus-transformed cell lines transfected with Marek's disease virus genes by virus-specific cytotoxic T cells. Vet. Immunol. Immunopathol. (in press). Versteeg, R., 1992. NK cells and T cells: mirror images? Immunol. Today 13:244-247. Weinstock, D., K. A. Schat, and B. W. Calnek, 1989. Cytotoxic T lymphocytes in reticuloendotheliosis virus-infected chickens. Eur. J. Immunol. 19: 267-272. Whitton, J. L., N. Sheng, M.B.A. Oldstone, and T. A. McKee, 1993. A "string-of-beads" vaccine, comprising linked minigenes, confers protection from lethal-dose virus challenge. J. Virol. 67: 348-352.
SYMPOSIUM: CURRENT ADVANCES IN AVIAN IMMUNOLOGY Yasukawa, M., and J. M. Zarling, 1984. Human cytotoxic T cell clones directed against herpes simplex virus-infected cells. I. Lysis restricted by HLC class II MB and DR antigens. J. Immunol. 133:422-427.
1081
Zoorob, R., A. Bernot, D. M. Renoir, F. Choukri, and C. Auffray, 1993. Chicken major histocomparibility complex class II B genes: analysis of interallelic and interlocus sequence variance. Eur. J. Immunol. 23:1139-1145.
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