A CD153+CD4+ T follicular cell population with cell-senescence features plays a crucial role in lupus pathogenesis via osteopontin production

J Immunol. 2015 Jun 15;194(12):5725-35. doi: 10.4049/jimmunol.1500319. Epub 2015 May 13.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • CD30 Ligand / metabolism
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism*
  • Cell Line
  • Cellular Senescence / immunology*
  • Disease Models, Animal
  • Female
  • Germinal Center / immunology
  • Germinal Center / metabolism
  • Immunophenotyping
  • Lupus Nephritis / immunology*
  • Lupus Nephritis / metabolism*
  • Lupus Nephritis / pathology
  • Lymphocyte Activation / immunology
  • Male
  • Mice
  • Osteopontin / biosynthesis*
  • Phenotype
  • Programmed Cell Death 1 Receptor / metabolism
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism

Substances

  • CD30 Ligand
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell
  • Osteopontin