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The efficiency of the human CD8+ T cell response: how should we quantify it, what determines it, and does it matter?

Elemans M, Seich Al Basatena NK, Asquith B - PLoS Comput. Biol. (2012)

Bottom Line: Multidisciplinary techniques, in particular the combination of theoretical and experimental immunology, can address questions about human immunity that cannot be answered by other means.From the turnover of virus-infected cells in vivo, to rates of thymic production and HLA class I epitope prediction, theoretical techniques provide a unique insight to supplement experimental approaches.Here we present our opinion, with examples, of some of the ways in which mathematics has contributed in our field of interest: the efficiency of the human CD8+ T cell response to persistent viruses.

View Article: PubMed Central - PubMed

Affiliation: Section of Immunology, Imperial College School of Medicine, London, United Kingdom.

ABSTRACT
Multidisciplinary techniques, in particular the combination of theoretical and experimental immunology, can address questions about human immunity that cannot be answered by other means. From the turnover of virus-infected cells in vivo, to rates of thymic production and HLA class I epitope prediction, theoretical techniques provide a unique insight to supplement experimental approaches. Here we present our opinion, with examples, of some of the ways in which mathematics has contributed in our field of interest: the efficiency of the human CD8+ T cell response to persistent viruses.

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Proposed mechanism to explain inhibitory KIR enhancement of HLA class I associations.KIR-HLA associations are typically attributed to direct NK action (a). However, Seich al Basatena's observations do not appear to be compatible with direct NK killing for four reasons. Firstly, most of the HLA molecules which were enhanced do not bind KIR2DL2. Secondly, both protective and detrimental HLA associations were enhanced. Thirdly, KIR2DL2 with or without its C1 ligand (i.e., not in the context of a particular protective or detrimental HLA allele) had no effect on any outcome for HCV or HTLV-1. And finally, the protective effect of binding HBZ was enhanced, and NK cells display some peptide specificity, but such marked protein specificity is more reminiscent of T cells [56]. Instead they hypothesise that the downstream effectors are CD8+ T cells (b). They postulate that KIR2DL2 enhances CD8+ T cell responses by increasing the survival of memory CD8+ T cells. Either because (i) inhibitory KIR on CD8+ T cells are associated with reduced activation induced cell death and protection from exhaustion [77]–[79] or (ii) inhibitory KIR on NK cells reduce NK-killing of activated CD8+ T cells [80], [81].
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pcbi-1002381-g002: Proposed mechanism to explain inhibitory KIR enhancement of HLA class I associations.KIR-HLA associations are typically attributed to direct NK action (a). However, Seich al Basatena's observations do not appear to be compatible with direct NK killing for four reasons. Firstly, most of the HLA molecules which were enhanced do not bind KIR2DL2. Secondly, both protective and detrimental HLA associations were enhanced. Thirdly, KIR2DL2 with or without its C1 ligand (i.e., not in the context of a particular protective or detrimental HLA allele) had no effect on any outcome for HCV or HTLV-1. And finally, the protective effect of binding HBZ was enhanced, and NK cells display some peptide specificity, but such marked protein specificity is more reminiscent of T cells [56]. Instead they hypothesise that the downstream effectors are CD8+ T cells (b). They postulate that KIR2DL2 enhances CD8+ T cell responses by increasing the survival of memory CD8+ T cells. Either because (i) inhibitory KIR on CD8+ T cells are associated with reduced activation induced cell death and protection from exhaustion [77]–[79] or (ii) inhibitory KIR on NK cells reduce NK-killing of activated CD8+ T cells [80], [81].

Mentions: Many associations between disease and pairs of KIR-HLA genes have been reported [62]–[66]. In each case the KIR-HLA pair consisted of a KIR with its HLA ligand and the effect was attributed to direct NK killing. What Seich al Basatena et al. observed is quite different. They found that associations between HLA class I molecules and disease outcome are weak in the absence of KIR2DL2 but are enhanced in the presence of KIR2DL2. This is true for multiple HLA-A, B, and C alleles, most of which do not bind KIR2DL2. They saw this effect in two different virus infections and for both protective and detrimental HLA associations. In contrast, KIR2DL2 with its HLA-C1 ligand (not in the context of protective or detrimental HLA molecules) has no detectable impact on any measure for either virus [56]. It is hard to reconcile these observations with direct NK killing (Figure 2a). Instead they hypothesised that KIR2DL2, a receptor typically associated with innate immunity, is enhancing the effectiveness of the CD8+ T cell response by increasing CD8+ T cell survival (Figure 2b). This is an example in which theory has suggested new biology: a novel role for an “innate” receptor in adaptive immunity.


The efficiency of the human CD8+ T cell response: how should we quantify it, what determines it, and does it matter?

Elemans M, Seich Al Basatena NK, Asquith B - PLoS Comput. Biol. (2012)

Proposed mechanism to explain inhibitory KIR enhancement of HLA class I associations.KIR-HLA associations are typically attributed to direct NK action (a). However, Seich al Basatena's observations do not appear to be compatible with direct NK killing for four reasons. Firstly, most of the HLA molecules which were enhanced do not bind KIR2DL2. Secondly, both protective and detrimental HLA associations were enhanced. Thirdly, KIR2DL2 with or without its C1 ligand (i.e., not in the context of a particular protective or detrimental HLA allele) had no effect on any outcome for HCV or HTLV-1. And finally, the protective effect of binding HBZ was enhanced, and NK cells display some peptide specificity, but such marked protein specificity is more reminiscent of T cells [56]. Instead they hypothesise that the downstream effectors are CD8+ T cells (b). They postulate that KIR2DL2 enhances CD8+ T cell responses by increasing the survival of memory CD8+ T cells. Either because (i) inhibitory KIR on CD8+ T cells are associated with reduced activation induced cell death and protection from exhaustion [77]–[79] or (ii) inhibitory KIR on NK cells reduce NK-killing of activated CD8+ T cells [80], [81].
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3285570&req=5

pcbi-1002381-g002: Proposed mechanism to explain inhibitory KIR enhancement of HLA class I associations.KIR-HLA associations are typically attributed to direct NK action (a). However, Seich al Basatena's observations do not appear to be compatible with direct NK killing for four reasons. Firstly, most of the HLA molecules which were enhanced do not bind KIR2DL2. Secondly, both protective and detrimental HLA associations were enhanced. Thirdly, KIR2DL2 with or without its C1 ligand (i.e., not in the context of a particular protective or detrimental HLA allele) had no effect on any outcome for HCV or HTLV-1. And finally, the protective effect of binding HBZ was enhanced, and NK cells display some peptide specificity, but such marked protein specificity is more reminiscent of T cells [56]. Instead they hypothesise that the downstream effectors are CD8+ T cells (b). They postulate that KIR2DL2 enhances CD8+ T cell responses by increasing the survival of memory CD8+ T cells. Either because (i) inhibitory KIR on CD8+ T cells are associated with reduced activation induced cell death and protection from exhaustion [77]–[79] or (ii) inhibitory KIR on NK cells reduce NK-killing of activated CD8+ T cells [80], [81].
Mentions: Many associations between disease and pairs of KIR-HLA genes have been reported [62]–[66]. In each case the KIR-HLA pair consisted of a KIR with its HLA ligand and the effect was attributed to direct NK killing. What Seich al Basatena et al. observed is quite different. They found that associations between HLA class I molecules and disease outcome are weak in the absence of KIR2DL2 but are enhanced in the presence of KIR2DL2. This is true for multiple HLA-A, B, and C alleles, most of which do not bind KIR2DL2. They saw this effect in two different virus infections and for both protective and detrimental HLA associations. In contrast, KIR2DL2 with its HLA-C1 ligand (not in the context of protective or detrimental HLA molecules) has no detectable impact on any measure for either virus [56]. It is hard to reconcile these observations with direct NK killing (Figure 2a). Instead they hypothesised that KIR2DL2, a receptor typically associated with innate immunity, is enhancing the effectiveness of the CD8+ T cell response by increasing CD8+ T cell survival (Figure 2b). This is an example in which theory has suggested new biology: a novel role for an “innate” receptor in adaptive immunity.

Bottom Line: Multidisciplinary techniques, in particular the combination of theoretical and experimental immunology, can address questions about human immunity that cannot be answered by other means.From the turnover of virus-infected cells in vivo, to rates of thymic production and HLA class I epitope prediction, theoretical techniques provide a unique insight to supplement experimental approaches.Here we present our opinion, with examples, of some of the ways in which mathematics has contributed in our field of interest: the efficiency of the human CD8+ T cell response to persistent viruses.

View Article: PubMed Central - PubMed

Affiliation: Section of Immunology, Imperial College School of Medicine, London, United Kingdom.

ABSTRACT
Multidisciplinary techniques, in particular the combination of theoretical and experimental immunology, can address questions about human immunity that cannot be answered by other means. From the turnover of virus-infected cells in vivo, to rates of thymic production and HLA class I epitope prediction, theoretical techniques provide a unique insight to supplement experimental approaches. Here we present our opinion, with examples, of some of the ways in which mathematics has contributed in our field of interest: the efficiency of the human CD8+ T cell response to persistent viruses.

Show MeSH
Related in: MedlinePlus