Immunity
Volume 1, Issue 4, July 1994, Pages 277-285
Journal home page for Immunity

Article
Disruption of T lymphocyte positive and negative selection in mice lacking the CD8 β chain

https://doi.org/10.1016/1074-7613(94)90079-5Get rights and content

Abstract

The CD4 and CD8 coreceptors have been shown to play significant roles in the differentiation and activation of helper and cytotoxic T lymphocytes (CTLs), respectively. Coordinate binding of coreceptor and T cell receptor (TCR) to the same major histocompatibility complex (MHC) molecule and coreceptor interaction with the tyrosine kinase p56lck are required for effective signaling. Whereas CD4 is a monomer, CD8 consists of either as homodimers or αβ heterodimers. Signaling properties of CD8 have been ascribed to the α chain, which binds to both the MHC class I and to p56lck, respectively. To study CD8β specifically, we have generated mice defective in its expression. We observe a significant reduction in the numbers of CD8+ T cells, but these cells have normal CTL activity. By breeding CD8βnull mice with animals expressing a class I-specific TCR transgene, we show that CD8β plays a significant role in both positive and negative selection of developing thymocytes.

References (55)

  • J.M. Turner et al.

    Interaction of the unique N-terminal region of tyrosine kinase p56lck with cytoplasmic domains of CD4 and CD8 is mediated by cysteine motifs

    Cell

    (1990)
  • A. Veillette et al.

    The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56lck

    Cell

    (1988)
  • V.A. Wallace et al.

    CD4, CD8 and tyrosine kinases in thymic selection

    Curr. Opin. Immunol.

    (1993)
  • H. Xu et al.

    A kinase-independent function of Lck in potentiating antigen-specific T cell activation

    Cell

    (1993)
  • C.J. Aldrich et al.

    Negative and positive selection of antigen-specific cytotoxic T lymphocytes affected by the a 3 domain of MHC I molecules

    Nature

    (1991)
  • P. Borgulya et al.

    Development of the CD4 and CD8 lineage T cells: instruction versus selection

    EMBO J.

    (1991)
  • A. Bradley

    Production and analysis of chimeric mice

  • I.N. Crispe et al.

    Expression and functional significance of the J11d marker on mouse thymocytes

    J. Immunol.

    (1987)
  • W.P. Fung-Leung et al.

    CD8 is needed for positive selection but differentially required for negative selection of T-cells during thymic ontogeny

    Eur. J. Immunol.

    (1993)
  • D. Guy-Grand et al.

    Two gut intraepithelial CD8` lymphocyte populations with different T cell receptors: a role for the gut epithelium in T cell differentiation

    J. Exp. Med.

    (1991)
  • A.L. Ingold et al.

    Co-engagement of CD8 with the T cell receptor is required for negative selection

    Nature

    (1991)
  • A. Itano et al.

    A role for the cytoplasmic tail of the chain in thymic selection

    Immunity

    (1994)
  • C.A. Janeway

    The T cell receptor as a multicomponent signaling machine

    Annu. Rev. Immunol.

    (1992)
  • N. Killeen et al.

    CD4 function in thymocyte differentiation and T cell activation

    Phil. Trans. R. Soc. Lond. B

    (1993)
  • N. Killeen et al.

    Requirement for CD8-MHC class I interaction in positive and negative selection of developing T cells

    J. Exp. Med.

    (1992)
  • P. Kisielow et al.

    Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+CD8+ thymocytes

    Nature

    (1988)
  • R. König et al.

    MHC class II interaction with CD4 mediated by a region analogous to the MHC class I binding site for CD8

    Nature

    (1992)
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