Positive selection of antigen-specific T cells in thymus by restricting MHC molecules

Kisielow, Paweł; Teh, Hung Sia; Blüthmann, Horst; Boehmer, Harald von

doi:10.1038/335730a0

Cited by 564 publications

(317 citation statements)

References 20 publications

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“…There are data that have been differentially interpreted to show that positive selection is either peptide specific (Ashton-Rickardt, 1993;Ashton-Rickardt and Tonegawa, 1994;AshtonRickardt et al, 1993;Goldrath and Bevan, 1999;Hogquist et al, 1994;Hsu et al, 1995;Nakano et al, 1997;Nikolic-Zugic and Bevan, 1990) or peptide-unspecific (Bachmann et al, 1993;Barnden et al, 1994;Berg et al, 1999;Ernst et al, 1999;Ignatowicz et al, 1996;Kisielow et al, 1988;Lee et al, 1999;Schumacher and Ploegh, 1994;Von Boehmer, 1994). The ambiguity of interpretation arises because peptide plays a role in the stability of R, in the expression of the allele-specific determinant, as well as in the specific signaling interaction with anti-P.…”

Section: Is Positive Selection [P+anti-p]-independent (Ie Peptide-mentioning

confidence: 99%

The Tritope Model for restrictive recognition of antigen by T-cells

Cohn

2008

Molecular Immunology

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Based on the Tritope model of the TCR (Cohn, 2005c), a set of functional and evolutionary problems surrounding restrictive recognition of antigen are discussed. These include the origin of allelespecific recognition, the selection pressures for polygeneism and polymorphism, the TCR signaling interactions, the centrality of effector T-helper (eTh)-dependence for activation, the role of haplotype exclusion, "nonclassical" MHC-elements, alloreactivity versus xenoreactivity, etc. Further, a set of observations believed to support the Standard Model are reinterpreted.A previous paper (Cohn, 2005c) detailed a new model (referred to as the Tritope Model) of the T-cell antigen-receptor (TCR) and analyzed its effectiveness in dealing with three basic phenomena, restrictive recognition, positive selection and allorecognition. The reasons for developing a model competing with the Standard Model have been discussed (Cohn, 2003;Cohn, 2004a;Cohn, 2004b;Cohn, 2006a;Langman and Cohn, 1999). Here we will extend the analysis of the Tritope Model by considering a set of phenomena related to the genetics, ontogeny and evolution of the TCR-MHC system. Further, the steps in the Self (S)-Nonself (NS) discrimination that are affected by the Tritope Model will be analyzed. Recalling the Tritope Model (Cohn, 2005c)The TCR encodes two distinctly different repertoires. One is germline-selected to recognize the allele-specific determinants (a) on the MHC-encoded restricting elements (R) of the species; the other is a somatically generated random repertoire that recognizes peptide (P) bound to the restricting element (R) as [PR].In order to map the two repertoires onto the TCR structure it was argued that (see List of Abbreviations):1. Single V-gene segments, Vα or Vβ, encode recognition of the allele-specific determinants (a). 2.Each domain (RI) or subunit (RII) of the R-element expresses an allele-specific determinant (a) (i.e., 2a per R).3. Peptide (P) is recognized by an anti-P site on the TCR formed by complementation of the CDR3 junctional regions of the α and β subunits.

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Section: Is Positive Selection [P+anti-p]-independent (Ie Peptide-mentioning

confidence: 99%

The Tritope Model for restrictive recognition of antigen by T-cells

Cohn

2008

Molecular Immunology

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“…Ag expression by cells having a hemopoietic origin is sufficient to drive negative selection because transfer of bone marrow (BM) 3 -derived cells from male transgenic (Tg) mice expressing a TCR specific for the male Ag into irradiated female recipients leads to effective deletion of thymocytes regardless of the MHC haplotype of the recipient (6). Intrathymic clonal deletion affects immature as well as semimature (CD4 ϩ CD8 Ϫ , HSA high ) thymocytes (7) and seems to require engagement of both TCR and costimulatory molecule receptors such as CD28 (5,8,9).…”

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confidence: 99%

Functional and Phenotypic Evidence for Presentation of Eα52–68 Structurally Related Self-Peptide(s) in I-Eα-Deficient Mice

Viret

Janeway

2000

The Journal of Immunology

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The Y-Ae mAb and the 1H3.1 TCR-αβ (Vα1/Vβ6) are two immune receptors specific for I-Ab MHC class II molecules complexed to the 52–68 fragment of the α-chain of I-E class II molecules (the Eα52–68 peptide). A profound intrathymic negative selection occurs in 1H3.1 TCR transgenic mice in the presence of an I-Eα transgene. The administration of mAbs to 1H3.1/I-Eα double-transgenic newborn mice reveals that Y-Ae, but not the isotype-matched anti-I-E Y17 mAb, rescues a significant number of mature (Vβ6highCD4+CD8−) thymocytes and allows the detection of Eα52–68-reactive T cells in the periphery. These observations indicate that deletion of autoreactive T cells can be specifically inhibited in vivo by an mAb specific for the deleting self-peptide:self-MHC class II complex. Similar inhibition experiments indicate that C57BL/6 (I-Ab+/I-Eα−) mice constitutively express an Eα-independent, Y-Ae-recognizable epitope(s). This finding is confirmed by the phenotypic analysis of mature (MHC class II high) C57BL/6 bone marrow-derived dendritic cells. Collectively, these observations further illustrate the peptide specificity of negative selection and demonstrate that MHC class II-positive cells from unmanipulated C57BL/6 mice that lack a functional I-Eα gene can assemble one or more self-peptide:I-Ab complexes recognizable by the Eα52–68:I-Ab complex-specific Y-Ae mAb.

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“…To investigate whether the HY-TCR could still ameliorate the developmental block at the b-selection point in the absence of its restricting MHC element, we bred the pTa -/-HY-I model onto the H-2 d background, which does not support positive selection of the HY-TCR [21]. Because the MHC and the pTa gene are located approximately 11 megabases apart on the same chromosome (www.ensembl.org) [22], mice had to be screened for a recombinant harboring the pTa-deficient allele on the same chromosome as H-2 d .…”

Section: Rescue Of Thymic Development In Tcr-transgenic Pta-deficientmentioning

confidence: 99%

MHC‐restricted T cell receptor signaling is required for αβ TCR replacement of the pre T cell receptor

et al. 2008

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A developmental block is imposed on CD25 + CD44 -thymocytes at the b-selection checkpoint in the absence of the pre T cell receptor (preTCR) a-chain, pTa. Early surface expression of a transgenic ab TCR has been shown to partially circumvent this block, such that thymocytes progress to the CD4 + CD8 + double-positive stage. We wanted to analyze whether a restricting MHC element is required for ab TCR-expressing doublenegative (DN) thymocytes to overcome the developmental block in pTa-deficient animals. We used the HY-I knock-in model that endows thymocytes with ab TCR expression in the DN compartment but has the advantage of physiological expression levels, in contrast to conventional TCR transgenes. On a pTa-deficient background, this HY-I TCR transgene 'rescued' CD25 + CD44 -thymocytes from apoptosis and enabled progression to later differentiation stages. On a non-selecting MHC background, however, pTa-deficient HY-I mice presented a pronounced reduction in numbers of splenocytes and thymocytes when compared to animals of selecting MHC genotype, showing that MHC restriction is necessary to drive HY-TCR-mediated rescue of pTa-deficient thymocytes.

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Positive selection of antigen-specific T cells in thymus by restricting MHC molecules

Cited by 564 publications

References 20 publications

The Tritope Model for restrictive recognition of antigen by T-cells

The Tritope Model for restrictive recognition of antigen by T-cells

Functional and Phenotypic Evidence for Presentation of Eα52–68 Structurally Related Self-Peptide(s) in I-Eα-Deficient Mice

MHC‐restricted T cell receptor signaling is required for αβ TCR replacement of the pre T cell receptor

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