Roots: Why affinity progression of antibodies during immune responses is probably not accompanied by parallel changes in the immunoglobulin‐like antigen‐specific receptors on T cells

Eisen, Herman N.

doi:10.1002/bies.950040609

Cited by 9 publications

(5 citation statements)

References 24 publications

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“…The VH186.2 gene utilized in combination with /I light chains in the response of C57BL/6 mice to the NP hapten is amongst the best studied examples at the molecular and cellular level (Bothwell et al 1981. Bothwell 1984, Cumano & Rajewsky 1985. 1986, Blier & Bothwell 1987, Allen et al 1987, Jacob et al 1991a) and we will discuss data from this system mainly involvitig NP-selected antibodies expressed in hybridomas.…”

Section: (B) Molecular Aspects Of Somatic Hypermutation Of Murine Ig mentioning

confidence: 99%

“…There are a variety of a priori arguments which seem to preclude a role for somatic hypermutation and thus affinity maturation in TcRs (Barth et al 1985, Eisen 1986, Dembic et al 1986). The first is the need to avoid the generation of overt autoimmune disease via anti-self MHC helper (TH) and cytotoxic (Tc) T cells.…”

Section: The a Priori Arguments As To Why T-cell Antigen-specific Recmentioning

confidence: 99%

“…Have there been enough genuine attempts to search for TcR somatic mutants by driving the T-cell response through in vivo immunization (Barth et al 1985, Fink et al 1986, Eisen 1986, Steele 1991b? There are now a series of well-defined examples which demonstrate clearly that T-cell clones established in vitro after in vivo priming show no evidence that their TcR Va and V^ genes utilized have undergone somatic hypermutation: for example TH clones specific for MHC class II and pigeon cytochrome-c (Fink et al 1986), sperm whale myoglobin peptides (Danska et al 1990, Sellins et al 1992, beef insulin (Wither et al 1991) and Tc clones specific for MHC class I and LCM virus peptides (Yanagi et al 1990).…”

Section: (A) Negative Reportsmentioning

confidence: 99%

“…In this review we will re-evaluate the evidence supporting the dominant view that T-cell antigen-specific receptors (TcRs) do not undergo somatic hypermutation (Barth et al 1985, Goverman et al 1986, Davis & Bjorkman 1988, Hackett et al 1992) and that T cells are therefore unlikely to undergo affinity maturation as occurs during the T-helper ceil (TH)-dependent differentiation of memory B cells (Eisen 1986). The process of somatic hypermutation in murine immunoglobulin (Ig) genes resulting in the selection of B cells with receptors of increasing affinity is now well defined (see Steele 1991a.…”

Section: Introductionmentioning

confidence: 99%

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Affinity Maturation of Lymphocyte Receptors and Positive Selection of T Cells in the Thymus

Steele

Rothenfluh

Ada

et al. 1993

Immunological Reviews

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In this review we have re-evaluated the dominant paradigm that TcR V genes do not somatically mutate. We highlight the many structural and functional similarities between Ig and TcR antigen-specific receptors on B and T cells. We have reviewed the factors influencing the somatic and germline evolution of IgV regions in B cells, have evaluated in detail various models which could be invoked to explain the pattern of variation in both transcribed and non-transcribed segments of germline IgV-gene DNA sequences, and applied this perspective to the TcR V beta and V alpha genes. Whilst specific TcRs recognize a complex of a short antigenic peptide bound to MHC Class I or II glycoprotein, and Ig receptors can recognize both oligopeptides and conformational determinants on undegraded polypeptides, they both employ heterodimer variable regions (Fabs) utilizing all three CDRs in epitope binding. We conclude that a plausible case can be made for the possibility that rearranged TcR V genes may undergo some type of somatic hypermutation process during T-cell development in the thymus (concurrent with or after the positive selection phase) thus allowing a repertoire of TvR alpha beta heterodimers to be both positively and negatively selected by the same set of ligands (self MHC + self peptide) in the thymus.

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Section: (B) Molecular Aspects Of Somatic Hypermutation Of Murine Ig mentioning

confidence: 99%

Section: The a Priori Arguments As To Why T-cell Antigen-specific Recmentioning

confidence: 99%

Section: (A) Negative Reportsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Affinity Maturation of Lymphocyte Receptors and Positive Selection of T Cells in the Thymus

Steele

Rothenfluh

Ada

et al. 1993

Immunological Reviews

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“…For example, negative selection acts to eliminate high TCR affinities. In addition, it has been hypothesized that there may be a ceiling on useful TCR–pMHC affinity (∼10 −7 M), above which there is no functional advantage ( 2 , 3 ) (and above which are possibly disadvantages, due to impaired serial triggering of TCRs [4]). Antibodies, which undergo affinity maturation, may have different functional ceilings on their affinity optimization ( 5 ).…”

mentioning

confidence: 99%

Effects of Complementarity Determining Region Mutations on the Affinity of an α/β T Cell Receptor: Measuring the Energy Associated with CD4/CD8 Repertoire Skewing

Manning

Parke

Teyton

et al. 1999

The Journal of Experimental Medicine

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It has been proposed that the generally low affinities of T cell receptors (TCRs) for their peptide–major histocompatibility complex (pMHC) ligands (Kd ∼10−4 to 10−7 M) are the result of biological selection rather than an intrinsic affinity limitation imposed by the TCR framework. Using a soluble version of the 2C TCR, we have used complementarity determining region (CDR)-directed mutagenesis to investigate whether the affinity of this receptor for its allogeneic pMHC ligand can be improved upon. We report that several mutants at positions lying within CDR3α and CDR2β showed increased affinities for pMHC compared with the wild-type receptor. Additionally, we have investigated whether Vα mutations that have been implicated in the phenomenon of CD8+ repertoire skewing achieve this skewing by means of generalized increases in affinity for MHC-I molecules. Two mutants (S27F and S51P), which each promote skewing toward a CD8+ phenotype, exhibited significantly reduced affinity for pMHC-I, consistent with a quantitative-instructional model of CD4/CD8 lineage commitment. This model predicts that CD8 is downregulated on thymocytes that have TCR–ligand interactions above a minimal energy threshold. Together, the results (a) demonstrate that engineering higher affinity TCRs is feasible, and (b) provide TCR–pMHC energy values associated with CD4/CD8 repertoire skewing.

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Immunization procedures forE. coli proteins

Anicetti¹,

Simonetti²,

Blackwood

et al. 1989

Appl Biochem Biotechnol

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Three immunization procedures were compared for the production of antibodies to the minor components of a complex E. coli protein (ECP) mixture: a conventional protocol and two methods that allow for the selective in vitro (cascade) or in vivo (passive) depletion of highly immunogenic proteins. An indirect ELISA showed that a maximum ELISA antibody titer was obtained with all the procedures 60 d after immunization. Analysis of these antisera by two-dimensional SDS-PAGE immunoblots, however, demonstrated that antibody reactivity to minor components in the mixture was not achieved until 112 d. This analysis also showed that a marked improvement in antibody response to minor components was obtained with the cascade immunization procedure. The mean titer and spectrum of antibody reactivity was similar for each group, and suggested that, although some individual variation was noted, the improvements observed were the result of the protocol used. Thus, for these ECPs, and multiple antigen mixtures in general, the preferred immunization protocol should employ at least three hosts and utilize the cascade immunization of Thalhamer and Freund. Characterization of the resulting antisera is best performed by use of silver stained two-dimensional SDS-PAGE and immunoblotting.

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Roots: Why affinity progression of antibodies during immune responses is probably not accompanied by parallel changes in the immunoglobulin‐like antigen‐specific receptors on T cells

Abstract: There can be no doubt that a closer study of avidity will be an indispensable step towards understanding the mechanisms of immunity. N. K. Jerne, 1951, p. 1403.

Cited by 9 publications

References 24 publications

Affinity Maturation of Lymphocyte Receptors and Positive Selection of T Cells in the Thymus

Affinity Maturation of Lymphocyte Receptors and Positive Selection of T Cells in the Thymus

Effects of Complementarity Determining Region Mutations on the Affinity of an α/β T Cell Receptor: Measuring the Energy Associated with CD4/CD8 Repertoire Skewing

Immunization procedures forE. coli proteins

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