The emergence of circulating activated autoreactive Dsg3-specific Tfr cells is associated with long-term efficacy of RTX in PV patients.

BACKGROUND: Pemphigus vulgaris (PV) is characterized by autoantibodies targeting keratinocytes adhesion proteins desmoglein (Dsg) 1 and 3, and by the HLA-DRB1-0402 predisposition allele. Treatment using rituximab (RTX) combined with short-term corticosteroids (CS) allows disease control and long-lasting remission. OBJECTIVE: The principal aim of this study is to evaluate the impact of RTX on the circulating subpopulations of Dsg-3-specific T lymphocytes that specifically regulate B cell responses: follicular helper (Tfh) and follicular regulatory T (Tfr) lymphocytes. METHODS: Using the HLA-DRB1-0402 tetramer loaded with the Dsg-3 immunodominant peptide, we analysed by flow cytometry the frequency, the polarisation and the activation status of blood Dsg-3-specific follicular T cell populations at baseline, Month 6 and long-term follow-up (Month 60-90) from PV patients. RESULTS: At baseline, we observed a predominance of Tfh1* and Tfh17 subsets and an underrepresentation of the Tfh2 subset among autoreactive Dsg-3-specific Tfh cells as compared with non-autoreactive Tfh cells. RTX treatment induced a decrease of autoreactive Tfh cells with no effect on their polarisation during patients' follow-up. In parallel, we observed the emergence of a Dsg-3-specific Tfr subpopulation with a significant overexpression of the surface activation markers PD1, ICOS, and CD25 that was not observed at the surface of autoreactive Tfh and non-autoreactive Tfr cells of the same PV patients. In contrast, a very few Dsg-3 specific Tfr cells were observed in PV patients treated with CS alone. CONCLUSION: Here we show that the emergence of circulating autoreactive Dsg-3-specific Tfr cells is associated with the long-term efficacy of RTX in PV patients.

Ageing of T-dependent B cell responses.

The human immune system is in continuous interaction with environmental factors (pathogens, exercise, stress, pollutants, diet, vaccines, and therapeutics) that condition its efficiency by promoting or moderating multiple immune mechanisms. While the deleterious impact of external factors can be avoided or limited, the immune system itself grows weaker with age. Immune cells persist in the elderly, and the observed decline of cellular immunity is related to cellular senescence. Immunosenescence, which affects both T and B cells, erodes lymphocyte-dependent responses to vaccines and pathogens. Germinal centers (GCs), the organized lymphoid structures where B cells engage in affinity maturation, are regulated by follicular helper (Tfh) and follicular regulatory (Tfr) T cells, the major T cell components of GCs. This review discusses how age-related changes affect Tfh and Tfr cells as key components of B cell immunity, and how they ultimately shape the response of the ageing immune system to vaccines and infectious challenges.

Ageing promotes early T follicular helper cell differentiation by modulating expression of RBPJ.

Ageing profoundly changes our immune system and is thought to be a driving factor in the morbidity and mortality associated with infectious disease in older people. We have previously shown that the impaired immunity to vaccination that occurs in aged individuals is partly attributed to the effect of age on T follicular helper (Tfh) cell formation. In this study, we examined how age intrinsically affects Tfh cell formation in both mice and humans. We show increased formation of Tfh precursors (pre-Tfh) but no associated increase in germinal centre (GC)-Tfh cells in aged mice, suggesting age-driven promotion of only early Tfh cell differentiation. Mechanistically, we show that ageing alters TCR signalling which drives expression of the Notch-associated transcription factor, RBPJ. Genetic or chemical modulation of RBPJ or Notch rescues this age-associated early Tfh cell differentiation, and increased intrinsic Notch activity recapitulates this phenomenon in younger mice. Our data offer mechanistic insight into the age-induced changes in T-cell activation that affects the differentiation and ultimately the function of effector T cells.

Evidence for tmTNF reverse signaling in vivo: Implications for an arginase-1-mediated therapeutic effect of TNF inhibitors during inflammation.

In order to ascertain the significance of transmembrane tumor necrosis factor (tmTNF) reverse signaling in vivo, we generated a triple transgenic mouse model (3TG, TNFR1-/-, TNFR2-/-, and tmTNFKI/KI) in which all canonical tumor necrosis factor (TNF) signaling was abolished. In bone-marrow-derived macrophages harvested from these mice, various anti-TNF biologics induced the expression of genes characteristic of alternative macrophages and also inhibited the expression of pro-inflammatory cytokines mainly through the upregulation of arginase-1. Injections of TNF inhibitors during arthritis increased pro-resolutive markers in bone marrow precursors and joint cells leading to a decrease in arthritis score. These results demonstrate that the binding of anti-TNF biologics to tmTNF results in decreased arthritis severity. Collectively, our data provide evidence for the significance of tmTNF reverse signaling in the modulation of arthritis. They suggest a complementary interpretation of anti-TNF biologics effects in the treatment of inflammatory diseases and pave the way to studies focused on new arginase-1-dependent therapeutic targets.