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IL-12-independent LIGHT signaling enhances MHC class II disparate CD4+ T cell alloproliferation, IFN-gamma responses, and intestinal graft-versus-host disease.

Abstract
Inhibition of LIGHT (a cellular ligand for herpes virus entry mediator and lymphotoxin receptor)/herpes simplex virus entry mediator (HVEM) and LIGHT/lymphotoxin beta receptor (LT beta R) interactions decreases mortality in MHC class I and II disparate graft-vs-host disease (GVHD). The present studies assessed the effects of these interactions on the generation of CD4+ T cell alloresponses in MHC class II-disparate MLC and GVHD. An inhibitor protein of LIGHT and LT alpha beta2 (LT beta R-Ig) and an inhibitor protein of LIGHT (HVEM-Ig) caused similar decreases in alloresponses of control B6 or B6.129S1-IL12rb2(tm1Jm) (B6.IL12R-/-) spleen cells (SpC) in a MHC class II-disparate MLC. GVHD-induced wasting disease in MHC class II-disparate recipients of B6 CD4+ SpC who received either the LT beta R-Ig-encoding adenovirus (LT beta R-Ig Adv; 13.1 +/- 10.9%; n = 10; p = 0.0004) or the HVEM-Ig-encoding adenovirus (HVEM-Ig Adv; 16.4 +/- 9.9%; n = 13; p = 0.0008) was significantly reduced compared with that in recipients of a control adenovirus (30.4 +/- 8.8%; n = 13). Furthermore, gut GVHD histologic scores of recipients of B6 CD4+ SpC who received the LT beta R-Ig Adv (0.8 +/- 0.8; n = 5; p = 0.0007) or the HVEM-Ig Adv (1.4 +/- 0.5; n = 5; p = 0.008) were reduced compared with scores of recipients of a control adenovirus (2.5 +/- 0.75; n = 11). In the intestine, both LT beta R-Ig Adv and HVEM-Ig Adv decreased CD4+ T cells (0.35 +/- 0.4 x 10(6) (n = 6) vs 0.36 +/- 0.02 x 10(6) (n = 9); p = 0.03 and p = 0.007) compared with control adenovirus (0.86 +/- 0.42 x 10(6); n = 9). LIGHT is critical for optimal CD4+ T cell alloresponses in MHC class II-disparate MLC and GVHD.
AuthorsGeri R Brown, Edward L Lee, Jihad El-Hayek, Katherine Kintner, Cheryl Luck
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 174 Issue 8 Pg. 4688-95 (Apr 15 2005) ISSN: 0022-1767 [Print] United States
PMID15814693 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • DNA, Recombinant
  • Histocompatibility Antigens Class II
  • Isoantigens
  • Membrane Proteins
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Member 14
  • Receptors, Virus
  • Recombinant Proteins
  • Tnfrsf14 protein, mouse
  • Tnfsf14 protein, mouse
  • Tumor Necrosis Factor Ligand Superfamily Member 14
  • Tumor Necrosis Factor-alpha
  • Interleukin-12
  • Interferon-gamma
Topics
  • Animals
  • Base Sequence
  • CD4-Positive T-Lymphocytes (cytology, immunology)
  • Cell Proliferation
  • DNA, Recombinant (genetics)
  • Female
  • Graft vs Host Disease (etiology, immunology)
  • Histocompatibility Antigens Class II (metabolism)
  • Interferon-gamma (biosynthesis)
  • Interleukin-12 (metabolism)
  • Intestines (immunology)
  • Isoantigens (metabolism)
  • Male
  • Membrane Proteins (immunology)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Receptors, Tumor Necrosis Factor (genetics, immunology)
  • Receptors, Tumor Necrosis Factor, Member 14
  • Receptors, Virus (genetics, immunology)
  • Recombinant Proteins (genetics, immunology)
  • Signal Transduction
  • Tumor Necrosis Factor Ligand Superfamily Member 14
  • Tumor Necrosis Factor-alpha (immunology)

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