Why Positive Selection?

Matzinger, Polly

doi:10.1111/j.1600-065x.1993.tb00645.x

Cited by 56 publications

(48 citation statements)

References 104 publications

(62 reference statements)

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“…Our results unequivocally show that the peptide proliferative response, which is predominantly CD4 ϩ T cell mediated, were restricted to the hematopoietic derived donor MHC-allele. The generally held belief is that the most efficacious method of T cell selection involves positive selection on MHCexpressing thymic epithelial cells (nonhematopoietic), followed by negative selection involving bone-marrow derived elements (17,18). However, this long-held view of exclusive T cell positive selection on radio-resistant thymic cells is under revision based on more recent studies suggesting that positive selection can occur on BM derived cells (10,(19)(20)(21), including fibroblasts or other MHC class II expressing cells in the thymic microenvironment (22)(23)(24).…”

Section: Mhc-restriction and T Cell Selectionmentioning

confidence: 99%

Purified hematopoietic stem cell allografts reconstitute immunity superior to bone marrow

Tsao

Allen

Logronio

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Antigen-specific immune responses are impaired after allogeneic hematopoietic cell transplantation (HCT). The events contributing to this impairment include host hematolymphoid ablation and donor cell regeneration, which is altered by pharmacologic immune suppression to prevent graft-versus-host disease (GVHD). A generally accepted concept is that graft T cell depletion performed to avoid GVHD yields poorer immune recovery because mature donor T cells are thought to be the major mediators of protective immunity early post-HCT. Our findings contradict the idea that removal of mature donor cells worsens immune recovery post-HCT. By transplantation of purified hematopoietic stem cells (HSC) compared with bone marrow (BM) across donor and recipient pairs of increasing genetic disparity, we show that grafts composed of the purified progenitor population give uniformly superior lymphoid reconstitution, both qualitatively and quantitatively. Subclinical GVHD by T cells in donor BM likely caused this lymphodepleting GVHD. We further determined in the major histocompatibility complex (MHC)-mismatched pairs, that T cell restricted proliferative responses were dictated by donor rather than host elements. We interpret these latter findings to show the importance of peripheral antigen presentation in the selection and maintenance of the T cell repertoire.immune reconstitution ͉ mice ͉ T cell selection

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Section: Mhc-restriction and T Cell Selectionmentioning

confidence: 99%

Purified hematopoietic stem cell allografts reconstitute immunity superior to bone marrow

Tsao

Allen

Logronio

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…First, alloreactive CD8 ϩ responses cannot be raised from ␤ 2 m Ϫ/Ϫ lymphoid tissues without prior in vivo immunization (12,14,15). Assuming a similar frequency of alloreactive TCRs within ␤ 2 m Ϫ/Ϫ and wild-type CD8 ϩ cells (the frequency of alloreactive cells is on average 1-10% in wild-type mice (18)), the frequency of alloreactive CD8 ϩ cells in total ␤ 2 m Ϫ/Ϫ spleen should be 5-100/10 4 cells. Even 10-fold lower frequencies (5-100/10 5 spleen cells) of Ag-specific CD8 ϩ cells from primed ␤ 2 m ϩ/ϩ mice readily produce detectable cytolytic responses after in vitro restimulation with Ag (19).…”

mentioning

confidence: 99%

αβTCR+ Cells Are a Minimal Fraction of Peripheral CD8+ Pool in MHC Class I-Deficient Mice

Nešić

Santori

Vukmanović

2000

The Journal of Immunology

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MHC class I molecules play a role in the maintenance of the naive peripheral CD8+ T cell pool. The mechanisms of the peripheral maintenance and the life span of residual CD8+ cells present in the periphery of β2-microglobulin-deficient (β2m−/−) mice are unknown. We here show that very few CD8+ cells in β2m−/− mice coexpress CD8β, a marker of the thymus-derived CD8+ T cells. Most of the CD8α+ cells express CD11c and can be found in β2m/RAG-2 double-deficient mice, demonstrating that these cells do not require rearranged Ag receptors for differentiation and survival and may be of dendritic cell lineage. Rare CD8α+CD8β+ cells can be detected following in vivo alloantigenic stimulation 2 wk after the adult thymectomy. Selective MHC class I expression by bone marrow-derived cells does not lead to an accumulation of CD8β+ cells in β2m−/− mice. These findings demonstrate that 1) thymic export of CD8+ T cells in β2m−/− mice is reduced more severely than previously thought; 2) non-T cells expressing CD8α become prominent when CD8+ T cells are virtually absent; 3) at least some β2m−/− CD8+ T cells have a life span in the periphery comparable to wild-type CD8+ cells; and 4) similar ligands induce positive selection in the thymus and survival of CD8+ T cells in the periphery.

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“…These findings suggest that positive selection reflects more the reaching of a quantitatively critical number of contacts between the TCR and its specific antigen presented on MHC class I or II (allele-independent) than of antigen-independent but MHC alleledependent contacts (1,2,(35)(36)(37)(38).…”

Section: Discussionmentioning

confidence: 90%

“…In parallel, splenocytes from day-8 immune chimeric and control mice were restimulated for 6 h with LCMV-gp [33][34][35][36][37][38][39][40][41] (gp33) or LCMV-np 118 -126 (np118) peptide, and CD8 ϩ T cells were analyzed for IFN-␥ secretion (Fig. 1B).…”

Section: Functional Cd8 ؉ T Cell Responses In B6-nude7balb͞c and B67bmentioning

confidence: 99%

“…Double tetramer stains with phycoerythrin-and allophycocyanin-labeled tetramers have been described (19). The LCMV-specific peptides [gp33 (gp [33][34][35][36][37][38][39][40][41] , KAVYNFATC), gp64 (gp 64 -80 , GPDIYKGVYQFKSVEFD), np396 (np 396 -404 , FQPQNGQFI), and np118 (np 118-126 , RPQASGVYM)] were synthesized by Neosystems (Strasbourg, France). Peptide stocks (10 Ϫ2 M) in DMSO were diluted 1͞1,000 and 1͞100,000 in medium for intracellular cytokine stains and for restimulations, respectively.…”

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confidence: 99%

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Functional CD8⁺but not CD4⁺T cell responses develop independent of thymic epithelial MHC

Martinic¹,

Broek²,

Rülicke

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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The role of nonthymic epithelial (non-TE) MHC in T cell repertoire selection remains controversial. To analyze the relative roles of thymic epithelial (TE) and non-TE MHC in T cell repertoire selection, we have generated tetraparental aggregation chimeras (B6-nude7BALB͞c and B67BALB͞c-nude) harboring T and B cells from both parents, whereas TE cells originated exclusively from the non-nude donor. These chimeras mounted protective virus-specific TE and non-TE MHC-restricted T cell responses. To further evaluate whether non-TE MHC alone was sufficient to generate a functional T cell repertoire, we generated tetraparental aggregation chimeras lacking MHC class II (B6-nude7MHCII ؊/؊ ) or both MHC molecules (B6-nude7MHCI ؊/؊ II ؊/؊ ) on TE cells, but not on cells of B6-nude origin. Chimeras with MHC-deficient TE cells mounted functional virus-specific CD8 ؉ but not CD4 ؉ T cell responses. Thus, maturation of functional CD4 ؉ T cell responses required MHC class II on thymic epithelium, whereas CD8 ؉ T cells matured in the absence of TE MHC. Although studies with nude mice reconstituted with a fully allogeneic thymus graft showed almost exclusive restriction to nude MHC alone, these studies were also not accepted because of suspected rescue of nude thymic rudiment (18). More recently, however, the availability of new tools and mice has allowed the controversial issue of the role of non-TE versus TE MHC in T cell repertoire selection to be readdressed. We had generated tetraparental aggregation chimeras from thymus-deficient nude mice and T and B celldeficient Rag Ϫ/Ϫ mice (19). In these Rag Ϫ/Ϫb 7nude d tetraparental aggregation chimeras TE cells were exclusively of Rag Ϫ/Ϫ H-2 b origin; however, T and B cells were exclusively of nude H-2 d origin. After infection of these chimeras with lymphocytic choriomeningitis virus (LCMV) or vesicular stomatitis virus (VSV), the MHC restriction and functionality of T cells were analyzed. Protective LCMV-specific CD8 ϩ T cell responses restricted to TE and non-TE MHC were detected in all chimeras tested. In addition, CD4 ϩ T cells restricted to non-TE MHC were present and functional as shown by the presence of high titers of CD4 ϩ T cell-dependent VSV-specific neutralizing antibodies comparable to those present in control mice. However, concerns emerged that T cells restricted to nude MHC in these chimeras might have had a survival advantage in the periphery over TE MHC-restricted T cells. It is well known that after leaving the thymus mature T cells are able to survive only in the periphery when their TCR remain in continuous interaction with TCR-restricting MHC molecules (20)(21)(22). In the periphery, mature T cells will primarily be in contact with their surrounding T and B cells, which in the Rag Ϫ/Ϫb 7nude d chimeras exclusively express nude MHC. Even if the nude MHC-restricted T cells after leaving the thymus were initially a minor population, in the periphery these T cells might have a survival advantage over the initially more numerous TE MHC-restricted T cells.Therefore,...

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Why Positive Selection?

Cited by 56 publications

References 104 publications

Purified hematopoietic stem cell allografts reconstitute immunity superior to bone marrow

Purified hematopoietic stem cell allografts reconstitute immunity superior to bone marrow

αβTCR+ Cells Are a Minimal Fraction of Peripheral CD8+ Pool in MHC Class I-Deficient Mice

Functional CD8⁺but not CD4⁺T cell responses develop independent of thymic epithelial MHC

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Why Positive Selection?

Cited by 56 publications

References 104 publications

Purified hematopoietic stem cell allografts reconstitute immunity superior to bone marrow

Purified hematopoietic stem cell allografts reconstitute immunity superior to bone marrow

αβTCR+ Cells Are a Minimal Fraction of Peripheral CD8+ Pool in MHC Class I-Deficient Mice

Functional CD8+but not CD4+T cell responses develop independent of thymic epithelial MHC

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Product

Resources

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Functional CD8⁺but not CD4⁺T cell responses develop independent of thymic epithelial MHC