PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of jexpmedHomeThe Rockefeller University PressEditorsContactInstructions for AuthorsThis issue
 
J Exp Med. 1995 February 1; 181(2): 641–648.
PMCID: PMC2191859

Greatly reduced lymphoproliferation in lpr mice lacking major histocompatibility complex class I

Abstract

Mice homozygous for the lpr gene have a defect in fas (CD95), a cell surface receptor that belongs to the tumor necrosis factor receptor family and that mediates apoptosis. This genetic abnormality results in lymphoproliferation characterized by the accumulation of CD4-CD8- (double negative [DN]) T cells, autoantibody production, and background strain-dependent, end-organ disease. Our previous results suggested that major histocompatibility complex (MHC) class I may be involved in the development of DN cells. To test this hypothesis, we derived C57BL/6-lpr/lpr (B6/lpr) mice that were deficient for the beta 2- microglobulin gene (beta 2m lpr) and had no detectable class I expression. At 6 mo of age, compared with B6/lpr littermates with normal class I genes, these mice showed greatly reduced lymphadenopathy, mostly due to a dramatic decrease in the number of DN cells. Significant changes in the percentage of other T cell subsets were noted, but only gamma/delta+ T cells showed a marked increase in both percentage and absolute numbers. Analysis of T cell receptor V beta expression of the remaining DN T cells in beta 2m -lpr mice showed a shift to a CD4-like repertoire from a CD8-like repertoire in control B6/lpr mice, indicating that a small MHC class II selected DN population was unmasked in lpr mice lacking class I. We also found that the production of immunoglobulin G (IgG) autoantibodies (antichromatin and anti-single stranded DNA), total IgG and IgG2a, but not total IgM or IgM rheumatoid factor, was significantly reduced in the beta 2m -lpr mice. This work suggests that >90% of DN T cells in lpr mice are derived from the CD8 lineage and are selected on class I. However, a T cell subset selected on class II and T cells expressing gamma/delta are also affected by the lpr defect and become minor components of the aberrant DN population.

Full Text

The Full Text of this article is available as a PDF (872K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Cohen PL, Eisenberg RA. Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease. Annu Rev Immunol. 1991;9:243–269. [PubMed]
  • Adachi M, Watanabe-Fukunaga R, Nagata S. Aberrant transcription caused by the insertion of an early transposable element in an intron of the Fas antigen gene of lpr mice. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1756–1760. [PubMed]
  • Watanabe-Fukunaga R, Brannan CI, Copeland NG, Jenkins NA, Nagata S. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature. 1992 Mar 26;356(6367):314–317. [PubMed]
  • Yonehara S, Ishii A, Yonehara M. A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor. J Exp Med. 1989 May 1;169(5):1747–1756. [PMC free article] [PubMed]
  • Miyawaki T, Uehara T, Nibu R, Tsuji T, Yachie A, Yonehara S, Taniguchi N. Differential expression of apoptosis-related Fas antigen on lymphocyte subpopulations in human peripheral blood. J Immunol. 1992 Dec 1;149(11):3753–3758. [PubMed]
  • Ogasawara J, Watanabe-Fukunaga R, Adachi M, Matsuzawa A, Kasugai T, Kitamura Y, Itoh N, Suda T, Nagata S. Lethal effect of the anti-Fas antibody in mice. Nature. 1993 Aug 26;364(6440):806–809. [PubMed]
  • Takahashi T, Tanaka M, Brannan CI, Jenkins NA, Copeland NG, Suda T, Nagata S. Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell. 1994 Mar 25;76(6):969–976. [PubMed]
  • Suda T, Takahashi T, Golstein P, Nagata S. Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell. 1993 Dec 17;75(6):1169–1178. [PubMed]
  • Ramsdell F, Seaman MS, Miller RE, Tough TW, Alderson MR, Lynch DH. gld/gld mice are unable to express a functional ligand for Fas. Eur J Immunol. 1994 Apr;24(4):928–933. [PubMed]
  • Kotzin BL, Babcock SK, Herron LR. Deletion of potentially self-reactive T cell receptor specificities in L3T4-, Lyt-2- T cells of lpr mice. J Exp Med. 1988 Dec 1;168(6):2221–2229. [PMC free article] [PubMed]
  • Herron LR, Eisenberg RA, Roper E, Kakkanaiah VN, Cohen PL, Kotzin BL. Selection of the T cell receptor repertoire in Lpr mice. J Immunol. 1993 Oct 1;151(7):3450–3459. [PubMed]
  • Singer PA, Balderas RS, McEvilly RJ, Bobardt M, Theofilopoulos AN. Tolerance-related V beta clonal deletions in normal CD4-8-, TCR-alpha/beta + and abnormal lpr and gld cell populations. J Exp Med. 1989 Dec 1;170(6):1869–1877. [PMC free article] [PubMed]
  • Landolfi MM, Van Houten N, Russell JQ, Scollay R, Parnes JR, Budd RC. CD2-CD4-CD8- lymph node T lymphocytes in MRL lpr/lpr mice are derived from a CD2+CD4+CD8+ thymic precursor. J Immunol. 1993 Jul 15;151(2):1086–1096. [PubMed]
  • Ohteki T, Seki S, Abo T, Kumagai K. Liver is a possible site for the proliferation of abnormal CD3+4-8- double-negative lymphocytes in autoimmune MRL-lpr/lpr mice. J Exp Med. 1990 Jul 1;172(1):7–12. [PMC free article] [PubMed]
  • Zhou T, Bluethmann H, Eldridge J, Berry K, Mountz JD. Origin of CD4-CD8-B220+ T cells in MRL-lpr/lpr mice. Clues from a T cell receptor beta transgenic mouse. J Immunol. 1993 Apr 15;150(8 Pt 1):3651–3667. [PubMed]
  • Steinberg AD, Roths JB, Murphy ED, Steinberg RT, Raveche ES. Effects of thymectomy or androgen administration upon the autoimmune disease of MRL/Mp-lpr/lpr mice. J Immunol. 1980 Aug;125(2):871–873. [PubMed]
  • Cohen PL, Eisenberg RA. The lpr and gld genes in systemic autoimmunity: life and death in the Fas lane. Immunol Today. 1992 Nov;13(11):427–428. [PubMed]
  • Bossu P, Singer GG, Andres P, Ettinger R, Marshak-Rothstein A, Abbas AK. Mature CD4+ T lymphocytes from MRL/lpr mice are resistant to receptor-mediated tolerance and apoptosis. J Immunol. 1993 Dec 15;151(12):7233–7239. [PubMed]
  • Singer GG, Abbas AK. The fas antigen is involved in peripheral but not thymic deletion of T lymphocytes in T cell receptor transgenic mice. Immunity. 1994 Aug;1(5):365–371. [PubMed]
  • Scott DE, Kisch WJ, Steinberg AD. Studies of T cell deletion and T cell anergy following in vivo administration of SEB to normal and lupus-prone mice. J Immunol. 1993 Jan 15;150(2):664–672. [PubMed]
  • Raulet DH. MHC class I-deficient mice. Adv Immunol. 1994;55:381–421. [PubMed]
  • Koller BH, Smithies O. Inactivating the beta 2-microglobulin locus in mouse embryonic stem cells by homologous recombination. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8932–8935. [PubMed]
  • Koller BH, Marrack P, Kappler JW, Smithies O. Normal development of mice deficient in beta 2M, MHC class I proteins, and CD8+ T cells. Science. 1990 Jun 8;248(4960):1227–1230. [PubMed]
  • Unkeless JC. Characterization of a monoclonal antibody directed against mouse macrophage and lymphocyte Fc receptors. J Exp Med. 1979 Sep 19;150(3):580–596. [PMC free article] [PubMed]
  • Ozato K, Hansen TH, Sachs DH. Monoclonal antibodies to mouse MHC antigens. II. Antibodies to the H-2Ld antigen, the products of a third polymorphic locus of the mouse major histocompatibility complex. J Immunol. 1980 Dec;125(6):2473–2477. [PubMed]
  • Sobel ES, Yokoyama WM, Shevach EM, Eisenberg RA, Cohen PL. Aberrant expression of the very early activation antigen on MRL/Mp-lpr/lpr lymphocytes. J Immunol. 1993 Jan 15;150(2):673–682. [PubMed]
  • Sobel ES, Kakkanaiah VN, Kakkanaiah M, Cheek RL, Cohen PL, Eisenberg RA. T-B collaboration for autoantibody production in lpr mice is cognate and MHC-restricted. J Immunol. 1994 Jun 15;152(12):6011–6016. [PubMed]
  • Morris SC, Cheek RL, Cohen PL, Eisenberg RA. Allotype-specific immunoregulation of autoantibody production by host B cells in chronic graft-versus host disease. J Immunol. 1990 Feb 1;144(3):916–922. [PubMed]
  • Sobel ES, Katagiri T, Katagiri K, Morris SC, Cohen PL, Eisenberg RA. An intrinsic B cell defect is required for the production of autoantibodies in the lpr model of murine systemic autoimmunity. J Exp Med. 1991 Jun 1;173(6):1441–1449. [PMC free article] [PubMed]
  • Sobel ES, Cohen PL, Eisenberg RA. lpr T cells are necessary for autoantibody production in lpr mice. J Immunol. 1993 May 1;150(9):4160–4167. [PubMed]
  • Asano T, Tomooka S, Serushago BA, Himeno K, Nomoto K. A new T cell subset expressing B220 and CD4 in lpr mice: defects in the response to mitogens and in the production of IL-2. Clin Exp Immunol. 1988 Oct;74(1):36–40. [PubMed]
  • Bill J, Kanagawa O, Linten J, Utsunomiya Y, Palmer E. Class I and class II MHC gene products differentially affect the fate of V beta 5 bearing thymocytes. J Mol Cell Immunol. 1990;4(5):269–280. [PubMed]
  • Liao NS, Maltzman J, Raulet DH. Positive selection determines T cell receptor V beta 14 gene usage by CD8+ T cells. J Exp Med. 1989 Jul 1;170(1):135–143. [PMC free article] [PubMed]
  • Kelley VE, Roths JB. Interaction of mutant lpr gene with background strain influences renal disease. Clin Immunol Immunopathol. 1985 Nov;37(2):220–229. [PubMed]
  • Giese T, Davidson WF. Chronic treatment of C3H-lpr/lpr and C3H-gld/gld mice with anti-CD8 monoclonal antibody prevents the accumulation of double negative T cells but not autoantibody production. J Immunol. 1994 Feb 15;152(4):2000–2010. [PubMed]
  • Bix M, Raulet D. Functionally conformed free class I heavy chains exist on the surface of beta 2 microglobulin negative cells. J Exp Med. 1992 Sep 1;176(3):829–834. [PMC free article] [PubMed]
  • Glas R, Ohlén C, Höglund P, Kärre K. The CD8+ T cell repertoire in beta 2-microglobulin-deficient mice is biased towards reactivity against self-major histocompatibility class I. J Exp Med. 1994 Feb 1;179(2):661–672. [PMC free article] [PubMed]
  • Jevnikar AM, Grusby MJ, Glimcher LH. Prevention of nephritis in major histocompatibility complex class II-deficient MRL-lpr mice. J Exp Med. 1994 Apr 1;179(4):1137–1143. [PMC free article] [PubMed]
  • Bix M, Coles M, Raulet D. Positive selection of V beta 8+ CD4-8- thymocytes by class I molecules expressed by hematopoietic cells. J Exp Med. 1993 Sep 1;178(3):901–908. [PMC free article] [PubMed]
  • Huang L, Crispe IN. Distinctive selection mechanisms govern the T cell receptor repertoire of peripheral CD4-CD8- alpha/beta T cells. J Exp Med. 1992 Sep 1;176(3):699–706. [PMC free article] [PubMed]
  • Raulet DH. The structure, function, and molecular genetics of the gamma/delta T cell receptor. Annu Rev Immunol. 1989;7:175–207. [PubMed]
  • Spriggs MK, Koller BH, Sato T, Morrissey PJ, Fanslow WC, Smithies O, Voice RF, Widmer MB, Maliszewski CR. Beta 2-microglobulin-, CD8+ T-cell-deficient mice survive inoculation with high doses of vaccinia virus and exhibit altered IgG responses. Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):6070–6074. [PubMed]
  • Jabs DA, Kuppers RC, Saboori AM, Burek CL, Enger C, Lee B, Prendergast RA. Effects of early and late treatment with anti-CD4 monoclonal antibody on autoimmune disease in MRL/MP-lpr/lpr mice. Cell Immunol. 1994 Mar;154(1):66–76. [PubMed]
  • Santoro TJ, Portanova JP, Kotzin BL. The contribution of L3T4+ T cells to lymphoproliferation and autoantibody production in MRL-lpr/lpr mice. J Exp Med. 1988 May 1;167(5):1713–1718. [PMC free article] [PubMed]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press