- Email: [email protected]
The biology of recognitive repertoires
TRENDS I M M U N O L O G Y TO D AY
hand, might generate tolerance due to abortive T-cell activation. Other factors that may influence the type of immune response generated are the antigen dose, its affinity to the T-cell receptor (TCR) and MHC, and the duration of the APC–T-cell contact. In this concept, it is the degree of DC activation/maturation, and not its origin or the nature of the activation stimulus, that is crucial for the type of immune response generated.
Concluding remarks In summary, distinct DC populations are now well characterized on the basis of their surface phenotype and ontogeny. However, it is less clear whether the outcome of the
immune response depends on antigen presentation by a specific type of DC, the nature of the DC activating signal, or the stage of DC maturation.
Owing to space limitations, only a small section of the conference is reviewed here. The authors wish to apologize to all presenters whose work was not mentioned.
Stephan Grabbe ([email protected]) is at the Dept of Dermatology, University of Münster, D-48149 Münster, Germany; Eckhart Kämpgen is at the Dept of Dermatology, University of Würzburg, D-97080 Würzburg, Germany; Gerold Schuler is at the Dept of Dermatology, University of Erlangen, D-91054 Erlangen, Germany.
References 1 Steinman, R.M. and J. Banchereau, J. (1998) Dendritic cells and the control of immunity. Nature 392, 245–252 2 Steinman, R.M. (1991) The dendritic cell system and its role in immunogenicity. Annu. Rev. Immunol. 9, 271–296 3 Reid, S.D. et al. (2000) The control of T cell responses by dendritic cell subsets. Curr. Opin. Immunol. 12, 114–121 4 Maldonado-Lopez, R. et al. (1999) CD8alpha1 and CD8alpha2 subclasses of dendritic cells direct the development of distinct T helper cells in vivo. J. Exp. Med. 189, 587–592 5 Vieira, P.L. et al. (2000) Development of Th1inducing capacity in myeloid dendritic cells requires environmental instruction. J. Immunol. 164, 4507–4512 6 Rissoan, M.C. et al. (1999) Reciprocal control of T helper cell and dendritic cell differentiation. Science 283, 1183–1186
The biology of recognitive repertoires Melvin Cohn By examining immunoglobulin (Ig) and T-cell receptor (TCR) gene loci
M
ost immunological meetings are not the place for a reflective discussion of conceptual frameworks or a balanced evaluation of the interpretation of data. This prompted Antonio Coutinho and Melvin Cohn to plan a series of meetings that gather together a handful of scientists with divergent views, chosen either because their body of work is considerable and/or because they display interests and insights directed towards a search for generalization. For our first meeting, we§ isolated ourselves in an inspiringly beautiful 16th century convent, where, sitting in council around a table, we centered our attention on the subject of the origin and nature of the recognitive repertoire. We allowed ourselves four days for relaxed presentations and discussions, which I will highlight prejudiciously – ignoring ‘who-said-what’ – to keep the ideas personality-free.
The B-cell repertoire The structure of the immunoglobulin (Ig) gene loci and the mechanisms of their
all the properties of the whole, which is what makes it the target of evolutionary selection. The number of Protectons, all equivalent, per individual is proportional to the size of that individual. The individual is protected per milliliter by a primary immune response to nonself that must reach an effective concentration in a short enough time without entraining a debilitating anti-self response. No matter what the mechanism of expression, in the end, it must produce a Protecton.
and their rearrangement patterns in many species, and by imposing evolutionary principles, we can determine fundamentals regarding the behavior and properties of recognitive repertoires. A recent meeting* addressed the opposing selection pressures that determine the size of the repertoire, the
Three rules of expression
characterization of specificity and the rules for effector function.
expression are vastly different in shark, chicken, rabbit, mouse and human, as the respective experts laid them out for us. How then, do they function as a single-minded humoral immune system? The immune system functions as a repeated series of protection units (termed ‘Protectons’). Each Protecton is the minimum unit of responsiveness that possesses
PII: S0167-5699(00)01677-7
There are three rules of expression, which state that: (1) secreted Ig must be aggregated by antigen to initiate effector function. In order for monomers (the limiting selection pressure on the repertoire) to aggregate Ig, they must be recognized by at least three antibodies. This means that the antigenunselected primary repertoire must be large enough to recognize most antigens in more than three ways. (2) In order for the response to reach an effective level in a short enough time, the repertoire must have two distributions of specificities: a small repertoire in 0167-5699/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved.
S E P T E M B E R *The First Gulbenkian Symposium on Immune Systems was held in Arrabida, Portugal, on 9–12 April 2000.
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TRENDS I M M U N O L O G Y T O D AY
high copy-number (HCN) and a large repertoire in low copy-number (LCN). These two repertoires interact synergistically: the HCN repertoire reaches a sufficient concentration in a short enough time but would miss too many pathogens; the LCN repertoire would respond too slowly but it would see almost everything – acting together, the response is adequate. (3) Although the specificity of the B-cell antigen-receptor (BCR) is driven solely by the necessity to make a self–nonself discrimination, haplotype (and isotype) exclusion is driven by the requirement for bivalency of Ig in order to mediate effector function. Monovalency owing to mixing of subunits by non-haplotype-excluded cells leads to termination of the aggregation reaction and accumulation of monomers (usually toxins) that cannot be eliminated. Whatever the gene arrangements, the mechanism of generation of the repertoire or its pathway of expression, all humoral immune systems must obey these three rules.
Origin of the HCN/LCN repertoires The HCN repertoire is determined by a small set of germline-selected V-genes that, by complementation (mouse or human) or conversion (chicken or rabbit), generate a larger set of germline-encoded but unselected specificities, anti-self and anti-nonself. This HCN repertoire is the substrate for somatic diversification by mutation or further conversion to generate the LCN repertoire. In species that generate their repertoires by gene conversion, special organs (gut-associated lymphoid tissue, GALT) are required to establish haplotype exclusion and for the generation of the HCN and LCN repertoires. However, repeated cycles of mutation or conversion in the absence of sequential antigenic selection eventually leads to garbage, so the generating organ must involute at some optimal time.
Facing the music In this framework, assigning large diversification factors like 107 to the complementaritydetermining region 3 (CDR3) of Ig, is an absurdity. A repertoire of 1010 different paratopes would be nonfunctional even in an elephant, not to mention a mouse with a total of 108 B cells. The amino-acid diversity
Box 1. Key outcomes Universals • Optimized repertoires must be small enough to respond in a sufficiently short time, yet large enough to recognize most pathogens. • The number of paratopes equals the number of epitopes, and vice versa. • Specificity is driven by the necessity to make a self–nonself discrimination. BCR • Antigens are combinatorial collections of epitopes. • A high copy-number and a low copy-number repertoire must interact to respond to a diverse set of pathogens in a short enough time. • Selection by monomers (toxins) determines the size of the repertoire as they must be seen by at least three antibodies of different specificity. • Haplotype exclusion is driven by the necessity to limit monovalency. TCR • Allele-specific recognition is germline-selected; peptide recognition is somatically selected. • Positive selection and alloreactivity involve allele-specific recognition, whereas restrictive reactivity requires, in addition, peptide recognition. • The anti-peptide (P) repertoire is capped at roughly 105.
in the region of Ig determined by the D-gene segment and N-additions needs analysis in another framework. This is to be contrasted with the T-cell antigen-receptor (TCR), where CDR3 is the only source of diversification of the anti-peptide (P) site and, even there, the size of its repertoire must be limited.
Three points were clearly defined but left unresolved Three questions remain: (1) is the signal from ligand binding to the BCR initiated by a conformational change or aggregation? The argument that monomers can signal B cells was countered by proposing nonspecific in vivo aggregation, but no mechanism was forthcoming; specific aggregation requires an antigen-independent generation of the repertoire of secreted Ig at a functional level in order to get started. (2) Is ‘receptor editing’ a selected property to reduce waste of cells undergoing negative selection or is it a manifestation of the leakiness of the STOP signal for haplotype exclusion? Here, a quantitative analysis would be key to showing that minimizing the waste due to negative selection can be significant. The waste due to low fusion efficiency alone is of the order of 70%; a mechanism to save a proportion of the anti-self cells, which is estimated to be ,1% of the total, seems unselectable. (3) Is DH functioning as a diversity or a §
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disaster element? The fact that DH is expressed in a preferred frame in functional Ig has not excited attention (although spectacular data in the rabbit can now be added to chicken and mouse), nor has the argument that the proposed ‘transcendental’ contribution of CDR3 to the repertoire is too much of a good thing.
The T-cell repertoire Surprisingly few facts are sufficient to define the requirements of a model for the TCR. Normally, the TCR undergoes two interactions, positive selection and restrictive recognition of peptide (which includes negative selection). In addition, abnormally, it undergoes alloreactivity, a high frequency phenomenon that could not have been directly evolutionarily selected but must be explained as an inevitable byproduct of restrictive recognition.
Two selection pressures operate on the combining sites of the TCR The selection pressures that operate on the combining sites of the TCR are that: first, the allele-specific recognition (anti-R) of the restricting element (R) must be germlineselected because no somatic process can know the allele-specific determinants (a) of a species; and, second, the peptide recognition (anti-P)
M. Cohn (San Diego, CA, USA), A. Coutinho (Oeiras, Portugal), M. Flajnik (Baltimore, MD, USA), S. Hedrick (San Diego, CA, USA), H. Hengartner (Zurich, Switzerland), K. Knight (Maywood, IL, USA), P. Kourilsky (Paris, France), D. Mason (Oxford, UK), E. Palmer (Basel, Switzerland), P. Parham (Stanford, CA, USA), M. Weigert (Princeton, NJ, USA), J-C. Weill (Paris, France), I. Wilson (San Diego, CA, USA) and H. Zachau (Munich, Germany).
TRENDS I M M U N O L O G Y TO D AY
must be somatically selected by the necessity to make a self–nonself discrimination.
A competing formulation A model of the TCR describes how the interactions of anti-R and anti-P with their respective ligands, R and P, result in a signal to the T-cell. As allele-specific determinants (a) are markers of the randomly complementing subunits of RII or the domains of RI, one can conclude that each VT-gene-segment encodes an anti-R that is specific for a given a. The anti-P is made up of (NJ)a–(NDNJ)b complementation. Positive selection operates on one subunit of the VaVb pair, to yield a restricted TCR that requires a (P 1 anti-P)-interaction to be signaled. The unselected subunit is responsible for alloreactivity.
Two predictions emerge First, in this framework, neither alloreactivity nor positive selection require a (P 1 antiP)-interaction. This conclusion was hotly
disputed as the popular affinity/avidity or standard model requires that they be (P 1 anti-P)-dependent. Settling this issue experimentally is critical. Second, from several considerations, such as the crossreactivity of anti-P, measurements of anti-P frequencies, and some structure/function requirements, it appears that the anti-P repertoire is capped at approximately 105 (roughly equal to the BCR repertoire of a Protecton). This conclusion would require that the self–nonself discrimination be based on sharp thresholds of PR density.
hard-core empiricists as philosophy, not science. Yet, unanimously we felt that the experience was so unique and rewarding that a series of future meetings along similar lines should be planned. Lastly, a way to open the discussions to a wider audience in an interactive way via the Internet was put on the agenda. A summary of the key outcomes of this meeting is shown in Box 1.
This meeting was organized while Melvin Cohn was Scholar-in-residence supported by a Fellowship (Praxis XXI/BCC/16443/98) at the Gulbenkian Science Institute (Oeiras, Portugal). It took courage on
Concluding remarks
the part of the Gulbenkian Foundation to support a
As regards our goal, how close did we come? Given the present day suspicion with which a search for the laws of immunology is viewed, it is obvious that we would need several meetings with overlapping participants to arrive at a point where what was said by one person would be appreciatively understood by the other. It takes time to communicate. Further, not all of us agreed with the goal, which was referred to by our
meeting that unashamedly set as its goal ‘understanding’. Their support affirmed that ascetic, thoughtful basic science is to be valued independent of whether utilitarian potential is discernable.
Melvin Cohn ([email protected]) is at the Salk Institute, Conceptual Immunology Group, La Jolla, CA 92037-1099, USA and is a regular visiting fellow at the Gulbenkian Science Institute, Oeiras, Portugal.
Immunology Today online Making the most of your personal subscription • •
High quality printouts (from PDF files) Links to other articles, other journals and cited software and databases
All you have to do is: • Obtain your subscription key from the address label of your print subscription • Then go to http://www.trends.com/free_access.html • Click on the large ‘Click Here’ button at the bottom of the page • You will see one of the following: (1) A BioMedNet login screen. If you see this, please enter your BioMedNet username and password. If you are not already a member please click on the ‘Join Now’ button and register. Once registered you will go straight to (2) below. (2) A box to enter a subscription key. Please enter your subscription key here and click on the ‘Enter’ button. • Once confirmed, go to http//IT.trends.com and view the full-text of Immunology Today If you get an error message please contact Customer Services ([email protected]) stating your subscription key and BioMedNet username and password. Please note that you do not need to re-enter your subscription key for MMT, BioMedNet ‘remembers’ your subscription. Institutional online access is available at a premium. If your institute is interested in subscribing to print and online please ask them to contact [email protected]
S E P T E M B E R Vo l . 2 1
No.9
2 0 0 0 435
hand, might generate tolerance due to abortive T-cell activation. Other factors that may influence the type of immune response generated are the antigen dose, its affinity to the T-cell receptor (TCR) and MHC, and the duration of the APC–T-cell contact. In this concept, it is the degree of DC activation/maturation, and not its origin or the nature of the activation stimulus, that is crucial for the type of immune response generated.
Concluding remarks In summary, distinct DC populations are now well characterized on the basis of their surface phenotype and ontogeny. However, it is less clear whether the outcome of the
immune response depends on antigen presentation by a specific type of DC, the nature of the DC activating signal, or the stage of DC maturation.
Owing to space limitations, only a small section of the conference is reviewed here. The authors wish to apologize to all presenters whose work was not mentioned.
Stephan Grabbe ([email protected]) is at the Dept of Dermatology, University of Münster, D-48149 Münster, Germany; Eckhart Kämpgen is at the Dept of Dermatology, University of Würzburg, D-97080 Würzburg, Germany; Gerold Schuler is at the Dept of Dermatology, University of Erlangen, D-91054 Erlangen, Germany.
References 1 Steinman, R.M. and J. Banchereau, J. (1998) Dendritic cells and the control of immunity. Nature 392, 245–252 2 Steinman, R.M. (1991) The dendritic cell system and its role in immunogenicity. Annu. Rev. Immunol. 9, 271–296 3 Reid, S.D. et al. (2000) The control of T cell responses by dendritic cell subsets. Curr. Opin. Immunol. 12, 114–121 4 Maldonado-Lopez, R. et al. (1999) CD8alpha1 and CD8alpha2 subclasses of dendritic cells direct the development of distinct T helper cells in vivo. J. Exp. Med. 189, 587–592 5 Vieira, P.L. et al. (2000) Development of Th1inducing capacity in myeloid dendritic cells requires environmental instruction. J. Immunol. 164, 4507–4512 6 Rissoan, M.C. et al. (1999) Reciprocal control of T helper cell and dendritic cell differentiation. Science 283, 1183–1186
The biology of recognitive repertoires Melvin Cohn By examining immunoglobulin (Ig) and T-cell receptor (TCR) gene loci
M
ost immunological meetings are not the place for a reflective discussion of conceptual frameworks or a balanced evaluation of the interpretation of data. This prompted Antonio Coutinho and Melvin Cohn to plan a series of meetings that gather together a handful of scientists with divergent views, chosen either because their body of work is considerable and/or because they display interests and insights directed towards a search for generalization. For our first meeting, we§ isolated ourselves in an inspiringly beautiful 16th century convent, where, sitting in council around a table, we centered our attention on the subject of the origin and nature of the recognitive repertoire. We allowed ourselves four days for relaxed presentations and discussions, which I will highlight prejudiciously – ignoring ‘who-said-what’ – to keep the ideas personality-free.
The B-cell repertoire The structure of the immunoglobulin (Ig) gene loci and the mechanisms of their
all the properties of the whole, which is what makes it the target of evolutionary selection. The number of Protectons, all equivalent, per individual is proportional to the size of that individual. The individual is protected per milliliter by a primary immune response to nonself that must reach an effective concentration in a short enough time without entraining a debilitating anti-self response. No matter what the mechanism of expression, in the end, it must produce a Protecton.
and their rearrangement patterns in many species, and by imposing evolutionary principles, we can determine fundamentals regarding the behavior and properties of recognitive repertoires. A recent meeting* addressed the opposing selection pressures that determine the size of the repertoire, the
Three rules of expression
characterization of specificity and the rules for effector function.
expression are vastly different in shark, chicken, rabbit, mouse and human, as the respective experts laid them out for us. How then, do they function as a single-minded humoral immune system? The immune system functions as a repeated series of protection units (termed ‘Protectons’). Each Protecton is the minimum unit of responsiveness that possesses
PII: S0167-5699(00)01677-7
There are three rules of expression, which state that: (1) secreted Ig must be aggregated by antigen to initiate effector function. In order for monomers (the limiting selection pressure on the repertoire) to aggregate Ig, they must be recognized by at least three antibodies. This means that the antigenunselected primary repertoire must be large enough to recognize most antigens in more than three ways. (2) In order for the response to reach an effective level in a short enough time, the repertoire must have two distributions of specificities: a small repertoire in 0167-5699/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved.
S E P T E M B E R *The First Gulbenkian Symposium on Immune Systems was held in Arrabida, Portugal, on 9–12 April 2000.
Vo l . 2 1
No.9
2 0 0 0 433
TRENDS I M M U N O L O G Y T O D AY
high copy-number (HCN) and a large repertoire in low copy-number (LCN). These two repertoires interact synergistically: the HCN repertoire reaches a sufficient concentration in a short enough time but would miss too many pathogens; the LCN repertoire would respond too slowly but it would see almost everything – acting together, the response is adequate. (3) Although the specificity of the B-cell antigen-receptor (BCR) is driven solely by the necessity to make a self–nonself discrimination, haplotype (and isotype) exclusion is driven by the requirement for bivalency of Ig in order to mediate effector function. Monovalency owing to mixing of subunits by non-haplotype-excluded cells leads to termination of the aggregation reaction and accumulation of monomers (usually toxins) that cannot be eliminated. Whatever the gene arrangements, the mechanism of generation of the repertoire or its pathway of expression, all humoral immune systems must obey these three rules.
Origin of the HCN/LCN repertoires The HCN repertoire is determined by a small set of germline-selected V-genes that, by complementation (mouse or human) or conversion (chicken or rabbit), generate a larger set of germline-encoded but unselected specificities, anti-self and anti-nonself. This HCN repertoire is the substrate for somatic diversification by mutation or further conversion to generate the LCN repertoire. In species that generate their repertoires by gene conversion, special organs (gut-associated lymphoid tissue, GALT) are required to establish haplotype exclusion and for the generation of the HCN and LCN repertoires. However, repeated cycles of mutation or conversion in the absence of sequential antigenic selection eventually leads to garbage, so the generating organ must involute at some optimal time.
Facing the music In this framework, assigning large diversification factors like 107 to the complementaritydetermining region 3 (CDR3) of Ig, is an absurdity. A repertoire of 1010 different paratopes would be nonfunctional even in an elephant, not to mention a mouse with a total of 108 B cells. The amino-acid diversity
Box 1. Key outcomes Universals • Optimized repertoires must be small enough to respond in a sufficiently short time, yet large enough to recognize most pathogens. • The number of paratopes equals the number of epitopes, and vice versa. • Specificity is driven by the necessity to make a self–nonself discrimination. BCR • Antigens are combinatorial collections of epitopes. • A high copy-number and a low copy-number repertoire must interact to respond to a diverse set of pathogens in a short enough time. • Selection by monomers (toxins) determines the size of the repertoire as they must be seen by at least three antibodies of different specificity. • Haplotype exclusion is driven by the necessity to limit monovalency. TCR • Allele-specific recognition is germline-selected; peptide recognition is somatically selected. • Positive selection and alloreactivity involve allele-specific recognition, whereas restrictive reactivity requires, in addition, peptide recognition. • The anti-peptide (P) repertoire is capped at roughly 105.
in the region of Ig determined by the D-gene segment and N-additions needs analysis in another framework. This is to be contrasted with the T-cell antigen-receptor (TCR), where CDR3 is the only source of diversification of the anti-peptide (P) site and, even there, the size of its repertoire must be limited.
Three points were clearly defined but left unresolved Three questions remain: (1) is the signal from ligand binding to the BCR initiated by a conformational change or aggregation? The argument that monomers can signal B cells was countered by proposing nonspecific in vivo aggregation, but no mechanism was forthcoming; specific aggregation requires an antigen-independent generation of the repertoire of secreted Ig at a functional level in order to get started. (2) Is ‘receptor editing’ a selected property to reduce waste of cells undergoing negative selection or is it a manifestation of the leakiness of the STOP signal for haplotype exclusion? Here, a quantitative analysis would be key to showing that minimizing the waste due to negative selection can be significant. The waste due to low fusion efficiency alone is of the order of 70%; a mechanism to save a proportion of the anti-self cells, which is estimated to be ,1% of the total, seems unselectable. (3) Is DH functioning as a diversity or a §
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Vo l . 2 1
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disaster element? The fact that DH is expressed in a preferred frame in functional Ig has not excited attention (although spectacular data in the rabbit can now be added to chicken and mouse), nor has the argument that the proposed ‘transcendental’ contribution of CDR3 to the repertoire is too much of a good thing.
The T-cell repertoire Surprisingly few facts are sufficient to define the requirements of a model for the TCR. Normally, the TCR undergoes two interactions, positive selection and restrictive recognition of peptide (which includes negative selection). In addition, abnormally, it undergoes alloreactivity, a high frequency phenomenon that could not have been directly evolutionarily selected but must be explained as an inevitable byproduct of restrictive recognition.
Two selection pressures operate on the combining sites of the TCR The selection pressures that operate on the combining sites of the TCR are that: first, the allele-specific recognition (anti-R) of the restricting element (R) must be germlineselected because no somatic process can know the allele-specific determinants (a) of a species; and, second, the peptide recognition (anti-P)
M. Cohn (San Diego, CA, USA), A. Coutinho (Oeiras, Portugal), M. Flajnik (Baltimore, MD, USA), S. Hedrick (San Diego, CA, USA), H. Hengartner (Zurich, Switzerland), K. Knight (Maywood, IL, USA), P. Kourilsky (Paris, France), D. Mason (Oxford, UK), E. Palmer (Basel, Switzerland), P. Parham (Stanford, CA, USA), M. Weigert (Princeton, NJ, USA), J-C. Weill (Paris, France), I. Wilson (San Diego, CA, USA) and H. Zachau (Munich, Germany).
TRENDS I M M U N O L O G Y TO D AY
must be somatically selected by the necessity to make a self–nonself discrimination.
A competing formulation A model of the TCR describes how the interactions of anti-R and anti-P with their respective ligands, R and P, result in a signal to the T-cell. As allele-specific determinants (a) are markers of the randomly complementing subunits of RII or the domains of RI, one can conclude that each VT-gene-segment encodes an anti-R that is specific for a given a. The anti-P is made up of (NJ)a–(NDNJ)b complementation. Positive selection operates on one subunit of the VaVb pair, to yield a restricted TCR that requires a (P 1 anti-P)-interaction to be signaled. The unselected subunit is responsible for alloreactivity.
Two predictions emerge First, in this framework, neither alloreactivity nor positive selection require a (P 1 antiP)-interaction. This conclusion was hotly
disputed as the popular affinity/avidity or standard model requires that they be (P 1 anti-P)-dependent. Settling this issue experimentally is critical. Second, from several considerations, such as the crossreactivity of anti-P, measurements of anti-P frequencies, and some structure/function requirements, it appears that the anti-P repertoire is capped at approximately 105 (roughly equal to the BCR repertoire of a Protecton). This conclusion would require that the self–nonself discrimination be based on sharp thresholds of PR density.
hard-core empiricists as philosophy, not science. Yet, unanimously we felt that the experience was so unique and rewarding that a series of future meetings along similar lines should be planned. Lastly, a way to open the discussions to a wider audience in an interactive way via the Internet was put on the agenda. A summary of the key outcomes of this meeting is shown in Box 1.
This meeting was organized while Melvin Cohn was Scholar-in-residence supported by a Fellowship (Praxis XXI/BCC/16443/98) at the Gulbenkian Science Institute (Oeiras, Portugal). It took courage on
Concluding remarks
the part of the Gulbenkian Foundation to support a
As regards our goal, how close did we come? Given the present day suspicion with which a search for the laws of immunology is viewed, it is obvious that we would need several meetings with overlapping participants to arrive at a point where what was said by one person would be appreciatively understood by the other. It takes time to communicate. Further, not all of us agreed with the goal, which was referred to by our
meeting that unashamedly set as its goal ‘understanding’. Their support affirmed that ascetic, thoughtful basic science is to be valued independent of whether utilitarian potential is discernable.
Melvin Cohn ([email protected]) is at the Salk Institute, Conceptual Immunology Group, La Jolla, CA 92037-1099, USA and is a regular visiting fellow at the Gulbenkian Science Institute, Oeiras, Portugal.
Immunology Today online Making the most of your personal subscription • •
High quality printouts (from PDF files) Links to other articles, other journals and cited software and databases
All you have to do is: • Obtain your subscription key from the address label of your print subscription • Then go to http://www.trends.com/free_access.html • Click on the large ‘Click Here’ button at the bottom of the page • You will see one of the following: (1) A BioMedNet login screen. If you see this, please enter your BioMedNet username and password. If you are not already a member please click on the ‘Join Now’ button and register. Once registered you will go straight to (2) below. (2) A box to enter a subscription key. Please enter your subscription key here and click on the ‘Enter’ button. • Once confirmed, go to http//IT.trends.com and view the full-text of Immunology Today If you get an error message please contact Customer Services ([email protected]) stating your subscription key and BioMedNet username and password. Please note that you do not need to re-enter your subscription key for MMT, BioMedNet ‘remembers’ your subscription. Institutional online access is available at a premium. If your institute is interested in subscribing to print and online please ask them to contact [email protected]
S E P T E M B E R Vo l . 2 1
No.9
2 0 0 0 435