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03.12 Tnfr2+regulatory t cells subpopulations are highly suppressive and are increased on anti-tnf treatment
  1. François Santinon1,
  2. Maxime Batignes1,
  3. Charlotte Pouchy2,
  4. Benoit Salomon2,
  5. Patrice Decker1,
  6. Marie-Christophe Boissier1,3,
  7. Luca Semerano1,3,
  8. Natacha Bessis1
  1. 1INSERM UMR 1125 Sorbonne Paris Cité, Université Paris, Bobigny, France
  2. 2Sorbonne Universités, UPMC Université Paris 06, INSERM, CNRS, Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
  3. 3Assistance Publique-Hôpitaux de Paris, Hôpital Avicenne, Service de Rhumatologie, Bobigny, France

Abstract

Background In rheumatoid arthritis (RA), regulatory T cells (Tregs) are defective in their suppressive capacities and fail to control chronic inflammation. TNF-α is involved in inhibition of Treg differentiation and activation, likely via activation of TNF type 1 receptor (TNFR1).1 Conversely, activation of TNFR2 on Tregs is critical for their phenotypic and functional stability in the inflammatory environment.2 Moreover, it has been shown that therapeutic TNF blockade with the anti-TNF monoclonal antibody adalimumab restores the potency of Treg cell suppression in RA by binding to membrane TNF- α on monocytes and promoting Treg cell expansion through enhanced TNFR2 signaling.3

In the present study we aimed to establish the role of TNFR2 on Tregs in control of inflammation at multiple levels, by: 1) studying the action of TNF on Treg function in the presence and absence of TNFR2 in vitro, 2) testing the severity of a model of skin inflammation in TNFR2KO mice, 3) evaluating the evolution of TNFR2-expressing Treg from RA patients during anti-TNF treatment.

Materials and methods Mice deficient in the TNFR2 gene (TNFR2 KO) and TNFR2 lox/lox mice to conditionally delete TNFR2 specifically in Tregs were used. CD4+CD25+Treg cells were purified by magnetic sorting. Cell phenotype was evaluated by flow cytometry. ATP concentrations were determined by luminometry. Skin inflammation was induced by applying an imiquimod-containing ointment, to the skin. Peripheral blood Treg where characterised before and after 3 months of anti–TNF treatment in 10 RA patients.

Results In vitro, TNF-α enhanced Foxp3 maintenance through TNFR2 signalling in cultured Tregs. In vivo, TNFR2-negative Treg cells, from both TNFR2KO and TNFR2 lox/lox mice, had lower spontaneous suppressive capacities (lower ATP hydrolysis, inhibition of effector T cells proliferation and IFN-γ production). Compared to wt mice, TNFR2KO mice had enhanced skin-inflammation and decreased Treg frequency in lymph nodes. In RA patients, TNF blockade induced an increase in the frequency of TNFR2-expressing Tregs at 3 months of treatment vs. the baseline

Conclusions TNFR2 signalling on Tregs may play a major role in controlling inflammation and can be activated both by TNF-α and anti-TNF treatment. Further studies to dissect TNFR2 dependent pathways on Tregs are warranted.

References

  1. Nie H, Zheng Y, Li R, et al. Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-α in rheumatoid arthritis. Nat Med2013;19:322-8.

  2. Chen X, Wu X, Zhou Q, et al. TNFR2 is critical for the stabilisation of the CD4+Foxp3+ regulatory T cell phenotype in the inflammatory environment. J Immunol. 2013;190:1076-84.

  3. Nguyen DX, Ehrenstein MR. Anti-TNF drives regulatory T cell expansion by paradoxically promoting membrane TNF-TNF-RII binding in rheumatoid arthritis. J Exp Med2016;213:1241-53.

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