Peptide Variants of Viral CTL Epitopes Mediate Positive Selection and Emigration of Ag-Specific Thymocytes In Vivo

Fridkis-Hareli, Masha; Reche, Pedro A.; Reinherz, Ellis L.

doi:10.4049/jimmunol.173.2.1140

Cited by 10 publications

(12 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The specificity of this effect is supported by the observation that the reconstitution of LMP7 Ϫ/Ϫ and WT mice with BM from St42 mice results in equally efficient selection of St42 T cells specific for an adenoviral peptide. OT-1 selection might not be completely abolished, because not only the Cp␣1 92-99 peptide but also additional peptides, as reported (27) reported an altered positive selection after i.v. injection of peptide variants, one might speculate that, after Cp␣1 injection, OT-1 T cells can be selected at a higher frequency, leave the thymus, and undergo normal homeostatic proliferation, explaining the elevated percentage of T cells even 180 days after Cp␣1 injection.…”

Section: Discussionmentioning

confidence: 83%

“…The i.v. injection of peptide variants of viral CTL epitopes had previously been reported to mediate the positive selection and emigration of antigen-specific thymocytes in vivo (27). Before and after three consecutive injections of the Cp␣1 92-99 peptide, we analyzed the numbers of CD8͞V␣2-positive T cells in the blood of OT-1 BM-transferred LMP7 Ϫ/Ϫ and WT mice at days 0, 14, 65, and 180.…”

Section: Deficiency In Selection Of Ot-1 T Cells After Ot-1 Bmt Into mentioning

confidence: 99%

See 1 more Smart Citation

Proteasomes shape the repertoire of T cells participating in antigen-specific immune responses

Osterloh

Linkemann

Tenzer

et al. 2006

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

View full text Add to dashboard Cite

Differences in the cleavage specificities of constitutive proteasomes and immunoproteasomes significantly affect the generation of MHC class I ligands and therefore the activation of CD8-positive T cells. Based on these findings, we investigated whether proteasomal specificity also influences CD8-positive T cells during thymic selection by peptides derived from self proteins. We find that one of the self peptides responsible for positive selection of ovalbuminspecific OT-1 T cells, which is derived from the f-actin capping protein (Cp␣1), is efficiently generated only by immunoproteasomes. Furthermore, OT-1 mice backcrossed onto low molecular mass protein 7 (LMP7)-deficient mice show a 50% reduction of OT-1 cells. This deficiency is also observed after transfer of BM from OT-1 mice in LMP7-deficient mice and can be corrected by the injection of the Cp␣1 peptide. Interestingly, WT and LMP7-deficient mice mount comparable immune responses to the ovalbumin-derived epitope SIINFEKL. However, their cytotoxic T lymphocytes (CTL) differ in the use of T cell receptor V␤ genes. CTL derived from WT mice use V␤8 or V␤5 (the latter is also used by OT-1 cells), whereas SIINFEKL-specific CTL from LMP7-deficient mice are exclusively V␤8-positive. Taken together, our experiments provide strong evidence that proteasomal specificity shapes the repertoire of T cells participating in antigen-specific immune responses. selection ͉ T cell repertoire C ytotoxic T lymphocytes (CTL) recognize a complex of MHC class I molecules and peptides derived mainly from intracellular proteins. The generation of these peptides crucially depends on the activity of proteasomes, which represent the main proteolytic activity present in the cytoplasm and are responsible for the generation of the C termini of most peptides presented by MHC class I molecules (1-5). The 20S proteasome represents the proteolytic core complex, which is composed of seven different ␣-and seven different ␤-subunits organized in a complex of four stacked rings with ␣ 7 ␤ 7 ␤ 7 ␣ 7 stoichiometry (6-8). The specificity of this protease is influenced by the incorporation of three IFN-inducible ␤-subunits (␤1i, ␤2i, and ␤5i), which replace the three proteolytically active constitutive subunits (␤1, ␤2, and ␤5) during proteasome assembly, resulting in the formation of so-called immunoproteasomes (9, 10). This type of proteasome generates reduced numbers of peptides with acid C termini and increased numbers of peptides with hydrophobic C termini (11,12), which is in favor of a more efficient transporter associated with antigen-presentation transport and binding to MHC class I molecules (13). In addition, a change in proteolytic specificity is apparent from the numerous examples reporting that either constitutive proteasomes or immunoproteasomes are required for the efficient generation of certain MHC class I ligands and consequently for the activation of CTL (14-19). As a result, proteasomal specificities provide a major contribution to the hierarchies of epitopes recognized by pathog...

show abstract

Section: Discussionmentioning

confidence: 83%

Section: Deficiency In Selection Of Ot-1 T Cells After Ot-1 Bmt Into mentioning

confidence: 99%

Proteasomes shape the repertoire of T cells participating in antigen-specific immune responses

Osterloh

Linkemann

Tenzer

et al. 2006

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

View full text Add to dashboard Cite

show abstract

“…The data described above and previously [40] represent the first examination of the direct effects of amino acid substitutions at the P14 and N15 TCR contact residues on thymocyte selection and emigration in vivo . In addition, we show that thymocyte emigration is dependent on the affinity/avidity of pMHC/TCR interactions.…”

Section: Discussionmentioning

confidence: 94%

“…In a similar way, D b / gp 33–41 vs. APL in which amino acid residues at p4 and p6 are altered, differentially affect development of thymocytes expressing the P14 TCR (data not shown). Experimental data using these APL (Y4S/F6A and A7E) for studies of thymocyte selection and emigration as applied to the thymic vaccination approach are summarized below (for the original work, see [40]).…”

Section: Discussionmentioning

confidence: 99%

“…To resolve this issue, we employed irradiation chimeras of congenic mouse strains (expressing the CD45.1 marker in B6 and CD45.2 in P14 and N15 transgenic mice) to determine whether interactions between the low affinity ligands, Y4S/F6A and L4, and their specific TCRs would result in thymic positive selection and subsequent emigration from the thymus. For this purpose, lineage-minus BM precursors of P14 – or N15- TCR transgenic Rag2 -/- mice (donor) were injected into irradiated congenic B6 mice (recipient) and the development of donor-type cells was monitored weekly by immunofluorescence staining and multicolor FACS analysis [40]. Following determination of the parameters related to the time period of appearance and the number of donor-type T cells in the chimeric thymus we administered the APL to the recipients at 3–4 wks after donor BM injection and assessed whether such exposure might influence the subsequent selection and emigration processes of donor thymocytes.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

New approaches to eliciting protective immunity through T cell repertoire manipulation: the concept of thymic vaccination

Fridkis-Hareli

Reinherz

2004

Med Immunol

Self Cite

View full text Add to dashboard Cite

Conventional vaccines afford protection against infectious diseases by expanding existing pathogenspecific peripheral lymphocytes, both CD8 cytotoxic effector (CTL) and CD4 helper T cells. The latter induce B cell maturation and antibody production. As a consequence, lymphocytes within the memory pool are poised to rapidly proliferate at the time of a subsequent infection. The "thymic vaccination" concept offers a novel way to alter the primary T cell repertoire through exposure of thymocytes to altered peptide ligands (APL) with reduced T cell receptor (TCR) affinity relative to cognate antigens recognized by those same TCRs. Thymocyte maturation (i.e. positive selection) is enhanced by low affinity interaction between a TCR and an MHC-bound peptide in the thymus and subsequent emigration of mature cells into the peripheral T lymphocyte pool follows. In principal, such variants of antigens derived from infectious agents could be utilized for peptidedriven maturation of thymocytes bearing pathogen-specific TCRs. To test this idea, APLs of gp [33][34][35][36][37][38][39][40][41] , a D b -restricted peptide derived from the lymphocytic choriomeningitis virus (LCMV) glycoprotein, and of VSV8, a K b -restricted peptide from the vesicular stomatitis virus (VSV) nucleoprotein, have been designed and their influence on thymic maturation of specific TCRbearing transgenic thymocytes examined in vivo using irradiation chimeras. Injection of APL resulted in positive selection of CD8 T cells expressing the relevant viral specificity and in the export of those virus-specific CTL to lymph nodes without inducing T cell proliferation. Thus, exogenous APL administration offers the potential of expanding repertoires in vivo in a manner useful to the organism. To efficiently peripheralize antigen-specific T cells, concomitant enhancement of mechanisms promoting thymocyte migration appears to be required. This commentary describes the rationale for thymic vaccination and addresses the potential prophylactic and therapeutic applications of this approach for treatment of infectious diseases and cancer. Thymic vaccinationinduced peptide-specific T cells might generate effective immune protection against disease-causing agents, including those for which no effective natural protection exists.

show abstract

Immunology in the clinic review series; focus on type 1 diabetes and viruses: enterovirus, thymus and type 1 diabetes pathogenesis

Jaïdane

Sané

Hiar

et al. 2012

Clinical and Experimental Immunology

View full text Add to dashboard Cite

Peptide Variants of Viral CTL Epitopes Mediate Positive Selection and Emigration of Ag-Specific Thymocytes In Vivo

Cited by 10 publications

References 55 publications

Proteasomes shape the repertoire of T cells participating in antigen-specific immune responses

Proteasomes shape the repertoire of T cells participating in antigen-specific immune responses

New approaches to eliciting protective immunity through T cell repertoire manipulation: the concept of thymic vaccination

Immunology in the clinic review series; focus on type 1 diabetes and viruses: enterovirus, thymus and type 1 diabetes pathogenesis

Contact Info

Product

Resources

About