- Email: [email protected]
Properties of antigens that determine processing
ImmunologyToday,vol. 7, No. 10, 1986
letlers MHC classII nomenclature in the rat
the requirement for processing. Finnegan eta/. 2 have shown that antigen stimulation, but not allostimulation of the same T-cell clone requires processing. Golding et al. demonSir, In their article on the evolution of strated two pathways for allostimuclass II genes (Immunol. Today, 1986, lation of CTL responses. Only the 7, 78-81) F. Figueroa and J. Klein's pathway that required cognate recocjdesignation of the class II loci of the nition also required processing ~. rat is incorrect. In the RT1 complex, Allen and Unanue have reported the the genes that encode class II anti- requirement for processing of native gens are designated RTI.B and hen egg lysozyme (HEL). However, RT1.D (Ref. 1). The RT1 .B and RT1 .D denatured carboxymethyl HEL or a antigens each consist of two tryptic digest of HEL4 did not require polypeptide chains, e and 13, and processing for presentation to one of they share homology with the H-2A two T-cell hybridomas. In addition and H-2E molecules, respectively, of they have concluded that a hydrothe mouse 2.3. The use of the des- philic T-cell determinant must be ignation 'RT1.A' and 'RT1.E c~,l~' is associated with a hydrophobic confusing because these letter des- region to allow peptides to associate ignations formally refer to the class I with the plasma membrane s. genes in the rat MHC (RT. 1A and Streicher et al. have also proposed RT. 1E)4. Because Klein has lent his that processing was necessary for considerable support to the current the association of antigen with RT1 nomenclature s, I am sure that membrane structures. Alloantigens, the authors' RT1 designations are an and possibly integral membrane prounfortunate oversight. I am also sure teins and some viral antigens may that the designation of H-2A and not require further processing for H-2E as 'H-2B" and "H-2D" by virtue presentation 6. Processing by proof their homology with the rat RT1 teolytic cleavage is the mechanism complex would not be acceptable cells use to alter protein structure for publication in many journals that allows interaction with membrane, class I and II molecules, and specializing in immunogenetics.
the T-cell receptor. Using this perspective, Berzofsky and DeLisi developed a computer model to predict amphipathic regions that also have a high probability of being recognized by T cells7. Thus, it is the size, conformation and physical structure of the antigen as well as the nature of the presenting cell and the T cell that determine processing requirements.
Howard Streicher Laboratoryof TumorCellBiology,National CancerInstitute, Bethesda,Maryland20892, USA
References 1 Streicher,H.Z., Berkower, I.J., Busch, M. et al. (1984)Proc. Natl Acad. Sci. USA 81, 6831 2 Finnegan,A., Needleman,B.W. and Hodes, R.J.(1985) J. Immunol. 134, 2960 3 Golding, H. and Singer, A. (1984) J. Immunol. 133, 597 4 Allen, P.M. and Unanue, E.R.(1984) J. Immunol. 132, 1077 5 Allen, P.M., Strydom, D.J.and Unanue, E.R. (1984) Immunology 81,2489 6 Streicher,H.Z., Berkower, I.J., Busch, M. et al. (1984)in Regulation of the Immune System, pp. 163-180, Alan R. Liss, Inc. 7 DeLisi,C. and Berzofsky,J.A. (1985) Proc. Natl Acad. Sci. USA 82, 7048
Donald V. Cramer Departmentof Pathology,Universityof PittsburghSchoolof Medicine,Pittsburgh, PA 15261,USA
References 1 Lobel, S.A. and Cramer, D.V. (1982) Immunogenetics 13,465-473 2 Blankenhorn, E.P.,Symington, F.W. and Cramer, D.V. (1983) Immunogenetics 17, 475-484 3 Blankenhorn, E.P.and Cramer, D.V. (1985) Immunogenetics 21, 135-142 4 Gill, T.J., Ill. Rat News Letter (1984) 12, 5-8 5 Klein, J., Rat News Letter (1985) 14, 3
Propertiesof antigensthat determine processing Sir,
290
The interesting review on antigen presentation by Grey and Chesnut (Immunol. Today, 1985, 6, 101-106) concludes with the suggestion that "it is the nature of the antigen that dictates the requirement for processing". Several reports not cited strongly support that view. Streicher et al." have shown that alteration of antigen conformation may bypass
we were able to demonstrate that immunization in vivo with H-43 a donor spleen cells induces specific and long-lasting (>200 days) antiH-43 a CTL tolerance in the H-43 b recipient mice2,3. Our results 3.4 supSir, Richard G. Miller (Immunol. Today, port neither the possibility of the 1986, 7, 112-114) stated that in- involvement of antigen=specific supactivation of T cells recognizing the pressor cells in self-tolerance, nor cell surface antigens on veto cells that crippled function of helper T (see Ref. 1) could be the mechanism cells (needed for differentiation of of maintenance of self-tolerance. He CTLp into functional CTL) is responsialso suggested that MHC-restriction ble. On the contrary, tolerance is in the inactivation of anti-self cyto- induced primarily at the level of antitoxic T-cell precursors (CTLp) by veto H-43 a CTLp and is best explained as cells should be proven. being caused by the veto mechanism4. Alan G. Herbert and James D. Furthermore, we have obtained eviWatson propose (Immunol. Today, dence that this veto cell-mediated 1986, 7, 72-76) that cells of a mixed anti-H-43 a CTL tolerance is induced killer/suppressor phenotype have the in the context of self-MHC class I molecules4. properties of veto cells. We have recently discovered a It is well-known that limited heteronew mouse minor H-43" antigen geneity in antigen epitopes is a key encoded by a locus at 8.5 centimor- factor in unmasking the fine Ir gene gans from the H-2 complex2. Using control on immune responses to recipient mice congenic with the protein antigens s. Our results 3'4 ,donor mice except at the H-43 locus, suggest that epitopes on an H-43 a antigen molecule recognized by * We renamedthe locus, formerlyH-42, H-43. anti-H-43 a CTLp are limited, and this MouseNewsLetter,in press. is why we were able to detect clearly
Specific and stable CTL tolerance induced by veto mechanism
Immunology Today, voL 7, No. 10, 1986
the veto cell-mediated inactivation of anti-H-43 a CTLp. This explanation is supported by the fact4 that the (anti-H-43 a) CTLp of H-43 b responder mice are primed by immunization with H-2 compatible H-43 a donor spleen cells carrying additional minor-H-alloantigens (e.g. H-Y antigen in the case of female H-43 b responder mice)4. This priming probably occurs via the process of linked recognition. If CTLp in the thymus are much more vulnerable to the veto mechanism than those in the spleen, due either to the unique thymic environment or to their cellu-
rostrum lar immaturity, the above rescue from the CTLp tolerance would not take place in the thymus. Consequently, the developing anti-self CTLp would be continuously eliminated in the thymus, and this, in conjunction with the concept of 'positive selection '6, may account in part for the massive cell death occurring in the thymus.
Hiromichi Ishikawa, Tomoo Hino, Hidehito Kato, Hiroko Suzuki and Kazuhisa Saito
Departmentof Microbiology,KeioUniversity Schoolof Medicine,Shinjuku-ku,Tokyo160, Japan
References 1 Muraoka, S., Ehman, D.L and Miller, R.G. (1984) Eur. J. Immunol. 14, 1010-1016 2 Ishikawa, H., Kubota, E., Suzuki, H. et a/. (1985)J. Immunol. 134, 2953-2959 3 Ishikawa, H., Suzuki, H., Hino, T. etaL (1985)2. Immunol. 135, 3681-3685 4 Ishikawa, H., Hino, T., Kato, H. etaL (1986) J. Immunol. 137 (in press) 5 Schwarz, R.H. (1986)Adv. ImmunoL 38, 31-201 6 Jerne, N.K. (1971 ) Eur. J. Immunol. 1, 1-9
HIV infection:facts and hypotheses The etiological agent of the acquired immunodeficiency syndrome (AIDS) was first isolated in 1983 and called lymphadenopathy associated virus (LAY)I. Other isolates of similar viruses have been named HTLV-III or ARV2'3. Numerous studies of their biological and molecular characteristics have confirmed that they are all different isolates of the same virus for which the name human immunodeficiency virus (HIV) has recently been proposed by an intemational committee 4. The current understanding of HIV's biological properties, supported by epidemiological and clinical observations, enables David Klatzmann and John Gluckman to propose a general model for its pathogenicity: a complex pathway of interaction between host and virus properties controls the stepwise evolution from primary infection to disease. Very low amounts of HIV infectious ~articles can be found in the serum, sperm, saliva, tears, or any other body fluid of an infected individual. This is probably why HIV is a poorly contagious virus and is almost exclusively transmitted via sexual contact or blood products. Indeed, except for massive injection of contaminated fluids (e.g. transfusion of plasma and factor VIII), we think that infection probably occurs more efficiently when infected lymphocytes are transmitted, each of them capable of producing thousands of viral particles. This also implies that allospecific T lymphocytes will be the first victims. Such a mode of infection has already been documented for the ovine lentivirus visna whose experimental infection is more easily obtained by injection of infected cells (G. Querat, unpublished). Of particular interest is the recent observation that the number of lymphocytes in the sperm is elevated in individuals with a history of repeated sexually transmitted diseasess. After exposure to HIV some individuals may resist infection, since 30% of the regular sex partners of infected patients do not show any evidence of infection 6. Animals models offer two possible explanations for such resistance:
Laboratoired'lmmunologieN~phrologiqueet Transplantation H(~pital, La Pitie-Salp~triere,75634ParisCedex13, France ~) 1986, Elsevier Science Publishers B.V., Amsterdam 0167 4919/86/$02 O0
D. Klatzmannand J.C. Gluckman (1) Sustained experimental bovine leukemia virus infection can be achieved by transmission of infected blood, but clearly depends on the inoculum size (A. Burny, unpublished). (2) After challenge with high doses of feline leukemia virus, approximately 30% of the cats resist infection without any evidence of specific cellular immune response, another 40% demonstrate a specific cellular and humoral response leading to immune protection, leaving only 30% to develop signs of chronic infection 7. With respect to these findings, it is possible that either an immune response or a classical non-specific clearance mechanism may protect against primary challenge with HIV.
Tropismof HIV Like most viruses HIV has preferential target cells in which it replicates after entering the organism. It was indeed the remarkable selective CD4 ÷ lymphocyte defect noted in AiDS patients8-1° that led us to investigate whether HIV displayed a selective tropism for CD4 ÷ lymphocytes: in vivo, HIV was only recovered from CD4 ÷ lymphocytes of infected patients, and only normal CD4 ÷ and not CD8 ÷ cells could be successfully infected in vitro 11. While HTLV-I, the first human retrovirus to be discovered, has also been claimed to display a CD4 + lymphotropism on the basis that HTLV-I infected cells are often CD4 +, recent experiments have demonstrated that CD8 ÷ lymphocytes are also infected and transformed by the virus 12. However, it has subsequently been noted that HIV can be present, or even replicate in various other cell types. Viral particles have thus been observed in normal B lymphocytes and cells of the monocytemacrophage lineage 13 , and HIV has been shown to actually replicate in some EBV-transformed B lymphoblastoid cell lines14 and cell lines of monocytic origin 1 2 1' 5 . Similarly, viral antigens or particles have been found in follicular dendritic cells of the lymphnode reticulum 16-18 and in cells of the brain 19, that are either passenger lymphocytes and monocytes, or microglial cells (Ref. 20, and R. Vazeux, unpublished)(Table 1).
291
-
letlers MHC classII nomenclature in the rat
the requirement for processing. Finnegan eta/. 2 have shown that antigen stimulation, but not allostimulation of the same T-cell clone requires processing. Golding et al. demonSir, In their article on the evolution of strated two pathways for allostimuclass II genes (Immunol. Today, 1986, lation of CTL responses. Only the 7, 78-81) F. Figueroa and J. Klein's pathway that required cognate recocjdesignation of the class II loci of the nition also required processing ~. rat is incorrect. In the RT1 complex, Allen and Unanue have reported the the genes that encode class II anti- requirement for processing of native gens are designated RTI.B and hen egg lysozyme (HEL). However, RT1.D (Ref. 1). The RT1 .B and RT1 .D denatured carboxymethyl HEL or a antigens each consist of two tryptic digest of HEL4 did not require polypeptide chains, e and 13, and processing for presentation to one of they share homology with the H-2A two T-cell hybridomas. In addition and H-2E molecules, respectively, of they have concluded that a hydrothe mouse 2.3. The use of the des- philic T-cell determinant must be ignation 'RT1.A' and 'RT1.E c~,l~' is associated with a hydrophobic confusing because these letter des- region to allow peptides to associate ignations formally refer to the class I with the plasma membrane s. genes in the rat MHC (RT. 1A and Streicher et al. have also proposed RT. 1E)4. Because Klein has lent his that processing was necessary for considerable support to the current the association of antigen with RT1 nomenclature s, I am sure that membrane structures. Alloantigens, the authors' RT1 designations are an and possibly integral membrane prounfortunate oversight. I am also sure teins and some viral antigens may that the designation of H-2A and not require further processing for H-2E as 'H-2B" and "H-2D" by virtue presentation 6. Processing by proof their homology with the rat RT1 teolytic cleavage is the mechanism complex would not be acceptable cells use to alter protein structure for publication in many journals that allows interaction with membrane, class I and II molecules, and specializing in immunogenetics.
the T-cell receptor. Using this perspective, Berzofsky and DeLisi developed a computer model to predict amphipathic regions that also have a high probability of being recognized by T cells7. Thus, it is the size, conformation and physical structure of the antigen as well as the nature of the presenting cell and the T cell that determine processing requirements.
Howard Streicher Laboratoryof TumorCellBiology,National CancerInstitute, Bethesda,Maryland20892, USA
References 1 Streicher,H.Z., Berkower, I.J., Busch, M. et al. (1984)Proc. Natl Acad. Sci. USA 81, 6831 2 Finnegan,A., Needleman,B.W. and Hodes, R.J.(1985) J. Immunol. 134, 2960 3 Golding, H. and Singer, A. (1984) J. Immunol. 133, 597 4 Allen, P.M. and Unanue, E.R.(1984) J. Immunol. 132, 1077 5 Allen, P.M., Strydom, D.J.and Unanue, E.R. (1984) Immunology 81,2489 6 Streicher,H.Z., Berkower, I.J., Busch, M. et al. (1984)in Regulation of the Immune System, pp. 163-180, Alan R. Liss, Inc. 7 DeLisi,C. and Berzofsky,J.A. (1985) Proc. Natl Acad. Sci. USA 82, 7048
Donald V. Cramer Departmentof Pathology,Universityof PittsburghSchoolof Medicine,Pittsburgh, PA 15261,USA
References 1 Lobel, S.A. and Cramer, D.V. (1982) Immunogenetics 13,465-473 2 Blankenhorn, E.P.,Symington, F.W. and Cramer, D.V. (1983) Immunogenetics 17, 475-484 3 Blankenhorn, E.P.and Cramer, D.V. (1985) Immunogenetics 21, 135-142 4 Gill, T.J., Ill. Rat News Letter (1984) 12, 5-8 5 Klein, J., Rat News Letter (1985) 14, 3
Propertiesof antigensthat determine processing Sir,
290
The interesting review on antigen presentation by Grey and Chesnut (Immunol. Today, 1985, 6, 101-106) concludes with the suggestion that "it is the nature of the antigen that dictates the requirement for processing". Several reports not cited strongly support that view. Streicher et al." have shown that alteration of antigen conformation may bypass
we were able to demonstrate that immunization in vivo with H-43 a donor spleen cells induces specific and long-lasting (>200 days) antiH-43 a CTL tolerance in the H-43 b recipient mice2,3. Our results 3.4 supSir, Richard G. Miller (Immunol. Today, port neither the possibility of the 1986, 7, 112-114) stated that in- involvement of antigen=specific supactivation of T cells recognizing the pressor cells in self-tolerance, nor cell surface antigens on veto cells that crippled function of helper T (see Ref. 1) could be the mechanism cells (needed for differentiation of of maintenance of self-tolerance. He CTLp into functional CTL) is responsialso suggested that MHC-restriction ble. On the contrary, tolerance is in the inactivation of anti-self cyto- induced primarily at the level of antitoxic T-cell precursors (CTLp) by veto H-43 a CTLp and is best explained as cells should be proven. being caused by the veto mechanism4. Alan G. Herbert and James D. Furthermore, we have obtained eviWatson propose (Immunol. Today, dence that this veto cell-mediated 1986, 7, 72-76) that cells of a mixed anti-H-43 a CTL tolerance is induced killer/suppressor phenotype have the in the context of self-MHC class I molecules4. properties of veto cells. We have recently discovered a It is well-known that limited heteronew mouse minor H-43" antigen geneity in antigen epitopes is a key encoded by a locus at 8.5 centimor- factor in unmasking the fine Ir gene gans from the H-2 complex2. Using control on immune responses to recipient mice congenic with the protein antigens s. Our results 3'4 ,donor mice except at the H-43 locus, suggest that epitopes on an H-43 a antigen molecule recognized by * We renamedthe locus, formerlyH-42, H-43. anti-H-43 a CTLp are limited, and this MouseNewsLetter,in press. is why we were able to detect clearly
Specific and stable CTL tolerance induced by veto mechanism
Immunology Today, voL 7, No. 10, 1986
the veto cell-mediated inactivation of anti-H-43 a CTLp. This explanation is supported by the fact4 that the (anti-H-43 a) CTLp of H-43 b responder mice are primed by immunization with H-2 compatible H-43 a donor spleen cells carrying additional minor-H-alloantigens (e.g. H-Y antigen in the case of female H-43 b responder mice)4. This priming probably occurs via the process of linked recognition. If CTLp in the thymus are much more vulnerable to the veto mechanism than those in the spleen, due either to the unique thymic environment or to their cellu-
rostrum lar immaturity, the above rescue from the CTLp tolerance would not take place in the thymus. Consequently, the developing anti-self CTLp would be continuously eliminated in the thymus, and this, in conjunction with the concept of 'positive selection '6, may account in part for the massive cell death occurring in the thymus.
Hiromichi Ishikawa, Tomoo Hino, Hidehito Kato, Hiroko Suzuki and Kazuhisa Saito
Departmentof Microbiology,KeioUniversity Schoolof Medicine,Shinjuku-ku,Tokyo160, Japan
References 1 Muraoka, S., Ehman, D.L and Miller, R.G. (1984) Eur. J. Immunol. 14, 1010-1016 2 Ishikawa, H., Kubota, E., Suzuki, H. et a/. (1985)J. Immunol. 134, 2953-2959 3 Ishikawa, H., Suzuki, H., Hino, T. etaL (1985)2. Immunol. 135, 3681-3685 4 Ishikawa, H., Hino, T., Kato, H. etaL (1986) J. Immunol. 137 (in press) 5 Schwarz, R.H. (1986)Adv. ImmunoL 38, 31-201 6 Jerne, N.K. (1971 ) Eur. J. Immunol. 1, 1-9
HIV infection:facts and hypotheses The etiological agent of the acquired immunodeficiency syndrome (AIDS) was first isolated in 1983 and called lymphadenopathy associated virus (LAY)I. Other isolates of similar viruses have been named HTLV-III or ARV2'3. Numerous studies of their biological and molecular characteristics have confirmed that they are all different isolates of the same virus for which the name human immunodeficiency virus (HIV) has recently been proposed by an intemational committee 4. The current understanding of HIV's biological properties, supported by epidemiological and clinical observations, enables David Klatzmann and John Gluckman to propose a general model for its pathogenicity: a complex pathway of interaction between host and virus properties controls the stepwise evolution from primary infection to disease. Very low amounts of HIV infectious ~articles can be found in the serum, sperm, saliva, tears, or any other body fluid of an infected individual. This is probably why HIV is a poorly contagious virus and is almost exclusively transmitted via sexual contact or blood products. Indeed, except for massive injection of contaminated fluids (e.g. transfusion of plasma and factor VIII), we think that infection probably occurs more efficiently when infected lymphocytes are transmitted, each of them capable of producing thousands of viral particles. This also implies that allospecific T lymphocytes will be the first victims. Such a mode of infection has already been documented for the ovine lentivirus visna whose experimental infection is more easily obtained by injection of infected cells (G. Querat, unpublished). Of particular interest is the recent observation that the number of lymphocytes in the sperm is elevated in individuals with a history of repeated sexually transmitted diseasess. After exposure to HIV some individuals may resist infection, since 30% of the regular sex partners of infected patients do not show any evidence of infection 6. Animals models offer two possible explanations for such resistance:
Laboratoired'lmmunologieN~phrologiqueet Transplantation H(~pital, La Pitie-Salp~triere,75634ParisCedex13, France ~) 1986, Elsevier Science Publishers B.V., Amsterdam 0167 4919/86/$02 O0
D. Klatzmannand J.C. Gluckman (1) Sustained experimental bovine leukemia virus infection can be achieved by transmission of infected blood, but clearly depends on the inoculum size (A. Burny, unpublished). (2) After challenge with high doses of feline leukemia virus, approximately 30% of the cats resist infection without any evidence of specific cellular immune response, another 40% demonstrate a specific cellular and humoral response leading to immune protection, leaving only 30% to develop signs of chronic infection 7. With respect to these findings, it is possible that either an immune response or a classical non-specific clearance mechanism may protect against primary challenge with HIV.
Tropismof HIV Like most viruses HIV has preferential target cells in which it replicates after entering the organism. It was indeed the remarkable selective CD4 ÷ lymphocyte defect noted in AiDS patients8-1° that led us to investigate whether HIV displayed a selective tropism for CD4 ÷ lymphocytes: in vivo, HIV was only recovered from CD4 ÷ lymphocytes of infected patients, and only normal CD4 ÷ and not CD8 ÷ cells could be successfully infected in vitro 11. While HTLV-I, the first human retrovirus to be discovered, has also been claimed to display a CD4 + lymphotropism on the basis that HTLV-I infected cells are often CD4 +, recent experiments have demonstrated that CD8 ÷ lymphocytes are also infected and transformed by the virus 12. However, it has subsequently been noted that HIV can be present, or even replicate in various other cell types. Viral particles have thus been observed in normal B lymphocytes and cells of the monocytemacrophage lineage 13 , and HIV has been shown to actually replicate in some EBV-transformed B lymphoblastoid cell lines14 and cell lines of monocytic origin 1 2 1' 5 . Similarly, viral antigens or particles have been found in follicular dendritic cells of the lymphnode reticulum 16-18 and in cells of the brain 19, that are either passenger lymphocytes and monocytes, or microglial cells (Ref. 20, and R. Vazeux, unpublished)(Table 1).
291
-