Fixing Mismatches

Shannon, Michele; Weigert, Martin

doi:10.1126/science.279.5354.1159

Cited by 9 publications

(7 citation statements)

References 10 publications

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“…This degeneracy in antigen recognition is typically associated with low-affinity interactions and is a hallmark of the preimmune B lymphocyte repertoire. It is via the processes of somatic mutation of B cell receptors and selection of antigen-reactivated B cells within germinal centers that B cell responses improve in both their affinity and fidelity for antigen recognition (12)(13)(14)(15)(16). This transition is paralleled by dramatic increases in both the association rate of the antigen-binding reaction and the structural rigidity of the receptors' antigen-binding site (9,17).…”

Section: Introductionmentioning

confidence: 94%

Developmental control of CD8+ T cell–avidity maturation in autoimmune diabetes

Han¹,

Serra²,

Yamanouchi³

et al. 2005

J. Clin. Invest.

100

108

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The progression of immune responses is generally associated with an increase in the overall avidity of antigenspecific T cell populations for peptide-MHC. This is thought to result from preferential expansion of high-avidity clonotypes at the expense of their low-avidity counterparts. Since T cell antigen-receptor genes do not mutate, it is puzzling that high-avidity clonotypes do not predominate from the outset. Here we provide a developmental basis for this phenomenon in the context of autoimmunity. We have carried out comprehensive studies of the diabetogenic CD8 + T cell population that targets residues 206-214 of the β cell antigen islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP 206-214 ) and undergoes avidity maturation as disease progresses. We find that the succession of IGRP 206-214 -specific clonotypes with increasing avidities during the progression of islet inflammation to overt diabetes in nonobese diabetic mice is fueled by autoimmune inflammation but opposed by systemic tolerance. As expected, naive high-avidity IGRP 206-214 -specific T cells respond more efficiently to antigen and are significantly more diabetogenic than their intermediate-or low-avidity counterparts. However, central and peripheral tolerance selectively limit the contribution of these high-avidity T cells to the earliest stages of disease without abrogating their ability to progressively accumulate in inflamed islets and kill β cells. These results illustrate the way in which incomplete deletion of autoreactive T cell populations of relatively high avidity can contribute to the development of pathogenic autoimmunity in the periphery. IntroductionThe diversity of the preimmune T and B cell repertoires is accomplished by random rearrangement of large arrays of V, D, and J genes during lymphocyte development. The encoded molecules fold into structures in which 6 hypervariable complementarity-determining regions (CDRs) are brought together to form the receptors' antigen-binding site (1, 2). A key common feature of the antigen-binding site of these receptors is its conformational flexibility, which affords ligand promiscuity (1-11). This degeneracy in antigen recognition is typically associated with low-affinity interactions and is a hallmark of the preimmune B lymphocyte repertoire. It is via the processes of somatic mutation of B cell receptors and selection of antigen-reactivated B cells within germinal centers that B cell responses improve in both their affinity and fidelity for antigen recognition (12-16). This transition is paralleled by dramatic increases in both the association rate of the antigen-binding reaction and the structural rigidity of the receptors' antigen-binding site (9,17).T cell responses usually undergo an analogous process of avidity maturation. Although there is some controversy as to the underlying kinetic mechanisms (i.e., avidity maturation proceeding through or only up to certain avidity thresholds), most studies concur that this process results from competitive survival of c...

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Section: Introductionmentioning

confidence: 94%

Developmental control of CD8+ T cell–avidity maturation in autoimmune diabetes

Han¹,

Serra²,

Yamanouchi³

et al. 2005

J. Clin. Invest.

100

108

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“…Quite astonishingly, while antibody diversification is perturbed by single deficiency in either UNG or MSH2, combined UNG/MSH2 deficiency completely abolishes switch recombination and hypermutation at dA:dT pairs [51]. Finally, mice mutant for EXO1, which participates in MMR as described above, have changes similar to those in MSH2-deficient mice [52].Previously, we suggested that MMR is co-opted in hypermutation by actively fixing mutations rather than repairing them, which may involve additional B cellspecific factors [23,42]. Here we analyze the influence of mismatch repair on hypermutation in non-B cells that ectopically express AID.…”

mentioning

confidence: 89%

“…Previously, we suggested that MMR is co-opted in hypermutation by actively fixing mutations rather than repairing them, which may involve additional B cellspecific factors [23,42]. Here we analyze the influence of mismatch repair on hypermutation in non-B cells that ectopically express AID.…”

Section: Introductionmentioning

confidence: 99%

“…In hypermutating B cells, the loss of MMR proteins, such as MLH1 and PMS2, results in a reduction of the mutation frequencies and in a change of the mutation pattern [44,45]. Consequently, we and others suggested an active contribution of MMR to hypermutation, for example fixing [23,42] or introducing [6,19] base mismatches. Physical association of MLH1 and EXO1 with the Ig V region but not the Ig constant (C) region in hypermutating BL2 cells supports this idea [6,19].…”

mentioning

confidence: 99%

“…But if the abasic site is not removed, any base can be introduced during replication [21]. Alternatively, although debated [22], mismatch repair (MMR) may sense G-U mispairing and set off a sequence of events that introduces further mutations rather than restore the original base pair sequence [23] (reviewed in [24]). …”

Section: Introductionmentioning

confidence: 99%

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Somatic hypermutation and mismatch repair in non-B cells

et al. 2005

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Mismatch repair contributes to hypermutation in B lymphocytes, both by increasing the frequency of mutations and by changing the mutational patterns. In this paper, we investigated whether or not mismatch repair influences activation-induced cytidine deaminase (AID)-mediated hypermutation in a non-B lymphocyte line. We did so by regulating expression of MutL homologue MLH 1, which is essential in mismatch repair, in a kidney cell line that had been transduced by an AID-containing vector. Whether or not MLH1 was expressed, we found no difference in the mutation rates of an indicator gene. We conclude that in order to contribute to hypermutation, mismatch repair needs additional factors that are present in activated B lymphocytes, but absent in the cell line investigated. IntroductionSomatic hypermutation contributes to antibody diversity through introduction of point mutations into the variable (V) region of immunoglobulin sequences [1]. The mutation rate in mice and humans is about 10 6 -fold higher than the spontaneous mutation rate in most other genes [2]. Targeting of somatic hypermutation to the Ig loci remains a subject of debate, since genomic sites other than the Ig loci have been reported to support hypermutation to various degrees [3][4][5][6]. However, somatic hypermutation is triggered by and restricted to the expression of the activation-induced cytidine deaminase (AID) enzyme in activated germinal center B cells [7][8][9][10]. Ectopic expression of AID in hybridomas [11], non-B cells [12,13] and even E. coli [14] results in a mutator phenotype. In conjunction with replication protein A (RPA) [15], AID acts on single-stranded DNA during transcription and deaminates dC into dU [16][17][18]. If the mismatch is not repaired, it results in a C?T transition, which is the predominant mutation during ectopic AID expression in cell lines and E. coli. After introduction of the G-U mismatch, various pathways fix the mutation in the genome (reviewed in [19]). For example, the uracil N-glycosylase (UNG) removes the uracil generated by AID [20]. If the resulting abasic site is converted by an AP-endonuclease into a singlestrand nick and subsequently repaired via the base excision pathway, no mutation is generated. But if the abasic site is not removed, any base can be introduced during replication [21]. Alternatively, although debated [22], mismatch repair (MMR) may sense G-U mispairing and set off a sequence of events that introduces further mutations rather than restore the original base pair sequence [23] (reviewed in [24] [39]. Cancer predisposition is linked to germ-line mutations in MMR genes; most mutations associated with HNPCC were found in hMLH1, hMSH2, and hMSH6 genes [40], while mutations in hPMS2 were reported sporadically. The majority of all HNPCC-causing mutations were found in hMLH1, focusing the interest on the analysis of pathogenic hMLH1 variants [41]. Although loss of EXO1, FEN1 and PCNA function also results in a mutator phenotype, it does not seem to significantly contribute to HNPCC forma...

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Antigen-Induced B-Lymphocyte Differentiation

Pillai¹

2000

Lymphocyte Development

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Fixing Mismatches

Cited by 9 publications

References 10 publications

Developmental control of CD8+ T cell–avidity maturation in autoimmune diabetes

Developmental control of CD8+ T cell–avidity maturation in autoimmune diabetes

Somatic hypermutation and mismatch repair in non-B cells

Antigen-Induced B-Lymphocyte Differentiation

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