Thymus dysfunction and chronic inflammatory disease in gp39 transgenic mice.
Expression of gp39 on activated T cells provides a co-stimulatory signal in peripheral lymphoid tissue that regulates humoral and cell-mediated immunity. The function of gp39 and its receptor CD40 in thymus remains uncertain. Here we report that overexpression of gp39 in transgenic mouse thymus caused a dose-dependent decline in thymocyte numbers (> 500 fold), loss of cortical epithelium and expansion of CD40+ medullary cells. Transplantation of transgenic bone marrow into normal mice indicated that gp39 significantly diminished thymocyte viability in the context of a 'normal' thymic environment. The peripheral tissues of transgenic mice also accumulated abnormalities in a transgene dose-dependent manner that involved inflammation and lymphoid tissue hypertrophy. Animals with the highest transgene copy numbers acquired a lethal inflammatory bowel disease marked by the infiltration of gp39+ T cells and CD40+ cells into diseased tissues. Examination of cells overexpressing gp39 suggested that these defects were caused, in part, by the saturation of a mechanism that sequesters gp39 inside non-activated cells and thus protects the immune system from inappropriate gp39-CD40 interaction. These results establish a regulatory role for gp39 in thymus function and a causal relationship in mediating chronic inflammatory disease.
Clegg
C H
CH
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121, USA.
Rulffes
J T
JT
Haugen
H S
HS
Hoggatt
I H
IH
Aruffo
A
A
Durham
S K
SK
Farr
A G
AG
Hollenbaugh
D
D
D000818:Animals; D019013:CD40 Antigens / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand; D002452:Cell Count; D002908:Chronic Disease; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D013950:Thymus Gland / Q000276:immunology* / Q000473:pathology / Q000502:physiology
D019013:CD40 Antigens; D008562:Membrane Glycoproteins; D023201:CD40 Ligand