The proteasome immunosubunit multicatalytic endopeptidase complex-like 1 is a T-cell-intrinsic factor influencing homeostatic expansion

Dietmar M W Zaiss, Natascha de Graaf, Alice J A M Sijts

    Research output: Contribution to journalArticleAcademicpeer-review

    Abstract

    Homeostatic regulatory mechanisms maintain the constant ratios between different lymphocyte subsets in the secondary lymphoid organs. How this dynamic equilibrium is achieved, in particular following the clonal expansion and subsequent contraction of different cells after infection, remains poorly understood. Expression of the proteasome immunosubunits has been shown to influence not only major histocompatibility complex class I (MHC-I) antigen processing and thereby T-cell responses, but also the CD4/CD8 T-cell ratios in lymphoid organs. We examined the relationships between these different immunosubunit-mediated effects in mice of various proteasome subunit compositions during infection with Listeria monocytogenes. Mice that lacked the immunosubunit multicatalytic endopeptidase complex-like 1 (MECL-1) maintained enhanced CD4/CD8 T-cell ratios during infection, while MHC-I surface levels resembled those in wild-type (wt) mice. LMP7 gene-deficient mice, on the other hand, showed reduced MHC-I expression, while their splenic CD4/CD8 ratios were similar to those in wt mice. Remarkably, analysis of bone marrow-chimeric immunosubunit gene-deficient mice, reconstituted with a mixture of wt and LMP7- plus MECL-1-deficient bone marrow, revealed that the LMP7- plus MECL-1-deficient T-cell population maintained a higher CD4/CD8 T-cell ratio than the wt T-cell population before, during, and after infection and T-cell memory formation. Since in these mice the immunosubunit-positive and immunosubunit-negative T-cell populations were selected in the same thymus and expanded in the same lymphoid environments, our findings indicate that MECL-1 influences the homeostatic equilibrium between T-cell subsets, not through indirect extracellular signals, such as MHC-I expression or the cytokine milieu, but through direct effects on T-cell-intrinsic processes.

    Original languageEnglish
    Pages (from-to)1207-1213
    Number of pages7
    JournalInfection and Immunity
    Volume76
    Issue number3
    DOIs
    Publication statusPublished - 2008

    Keywords

    • Adoptive Transfer
    • Animals
    • CD4-CD8 Ratio
    • Cysteine Endopeptidases
    • Female
    • Histocompatibility Antigens Class I
    • Interferon-gamma
    • Listeria monocytogenes
    • Lymphocyte Depletion
    • Mice
    • Mice, Knockout
    • Multienzyme Complexes
    • Proteasome Endopeptidase Complex
    • Spleen
    • T-Lymphocyte Subsets
    • T-Lymphocytes
    • Journal Article
    • Research Support, N.I.H., Extramural
    • Research Support, Non-U.S. Gov't

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