Ex vivo homeostatic proliferation of CD4+ T cells in rheumatoid arthritis is dysregulated and driven by membrane-anchored TNFalpha.
The systemic CD4(+) T cell compartment in patients with rheumatoid arthritis (RA) is characterized by TCR repertoire contraction, shortened telomere lengths, and decreased numbers of recent thymic emigrants, suggesting a disturbed CD4(+) T cell homeostasis. In mice, homeostatic proliferation of peripheral CD4(+) T cells is regulated by TCR interaction with self peptide-MHC complexes (pMHC) and can be reproduced in vitro. We have established an ex vivo model of homeostatic proliferation, in which self-replication of human CD4(+) T cells is induced by cell-cell contact with autologous monocytes. In healthy individuals, blockade of TCR-pMHC class II contact resulted in decreased CD4(+) T cell division. In contrast, homeostatic proliferation in RA patients was not inhibited by pMHC blockade, but increased during the initial culture period. The anti-TNF-alpha Ab cA2 inhibited homeostasis-driven ex vivo proliferation in healthy controls and in RA patients. In addition, treatment of RA patients with infliximab decreased the ex vivo rate of homeostatic proliferation of CD4(+) T cells. Our results suggest a disturbed regulation of CD4(+) T cell homeostasis leading to the repertoire aberrations reported in RA. Membrane-anchored TNF-alpha appears to be a cell-cell contact-dependent stimulus of homeostatic proliferation of CD4(+) T cells, possibly favoring self-replication of autoreactive CD4(+) T cells in patients with RA.
Department of Medicine IV, University of Leipzig, Leipzig, Germany. wagu@medizin.uni-leipzig.de
Ulf
U
Wagner
Matthias
M
Pierer
Matthias
M
Wahle
Falk
F
Moritz
Sylke
S
Kaltenhäuser
Holm
H
Häntzschel
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018501:Antirheumatic Agents / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D002450:Cell Communication / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002462:Cell Membrane / Q000737:chemistry / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D000069285:Infliximab; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D000949:Histocompatibility Antigens Class II; D018950:Lipopolysaccharide Receptors; D011948:Receptors, Antigen, T-Cell; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab