A CD153+CD4+ T Follicular Cell Population with Cell-Senescence Features Plays a Crucial Role in Lupus Pathogenesis via Osteopontin Production
2015
Immune aging results in diminished adaptive immunity and increased risk for autoimmunity. We previously reported a unique PD-1 + CD44 high CD4 + T cell population that increases with age in normal mice. In this study, we indicate that the age-dependent PD-1 + CD44 high CD4 + T cells develop as unique T follicular (TF) cells in a B cell–dependent manner and consist of two subpopulations, as follows: CD153 + cells preferentially secreting abundant osteopontin on TCR stimulation and CD153 − cells that are apparently TCR anergic. These unique TF cells with essentially similar features increase much earlier and are accumulated in the spontaneous germinal centers (GCs) in lupus-prone female BWF1 (f-BWF1) mice. These TF cells showed characteristic cell-senescence features and developed in association with extensive CD4 + T cell proliferation in vivo, suggesting replicative senescence. Although the CD153 + TF cells were defective in proliferation capacity, they were quite stable and specifically responded to self GC-B cells to secret abundant osteopontin, which inhibited B cell receptor–induced GC-B cell apoptosis in f-BWF1 mice. Transfer of CD153 + PD-1 + CD4 + T cells promoted the growth of spontaneous GCs, whereas administration of anti-osteopontin Ab suppressed GC enlargement and anti-nuclear Ab production and ameliorated clinical lupus nephritis of f-BWF1 mice. Current results suggest that senescent CD153 + TF cells generated as a consequence of extensive endogenous CD4 + T cell proliferation play an essential, if not sufficient, role in lupus pathogenesis in lupus-prone genetic background and may also contribute to an increased autoimmunity risk with age.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
42
References
55
Citations
NaN
KQI