Comparative Study of Senescent Th Biomarkers in Healthy Donors and Early Arthritis Patients. Analysis of VPAC Receptors and Their Influence.

Raúl Villanueva-Romero,Carmen Martínez,Selene Pérez-García,Marissa Flores-Santamaría,Ana Triguero-Martínez,Mar Carrión,Rosa P Gomariz,Amalia Lamana,José L Pablos,Isidoro González-Álvaro,Irene Gutiérrez-Cañas,Gabriel Criado,Eva Tomero,Yasmina Juarranz

doi:10.3390/cells9122592

Abstract

Pro-inflammatory CD4+CD28− T cells are characteristic of immunosenescence, but also of several autoimmune/inflammatory diseases. Vasoactive intestinal peptide (VIP) acts as an anti-inflammatory and immunomodulatory mediator on these cells. Our objective was to study the mutual influence between senescent Th cells and VIP axis in early arthritis (EA), comparing with non-EA donors. We characterized the correlation between senescent Th cells and clinic parameters of EA as well as the behavior of senescent Th biomarkers by real-time PCR. Clinical data were systematically recorded at baseline and after 6 months of follow-up. The number of CD4+CD28− T cells measured by sorting is higher in patients who initially meet ACR classification criteria for rheumatoid arthritis (RA) compared to those who were classified as undifferentiated arthritis (UA). A slight positive correlation between EA CD4+CD28− T cells and CRP or ESR and a negative correlation with bone mineral density were found. Th senescent biomarkers in EA CD4+CD28− T cells were similar to donors, however some of them increased after 6 months of follow-up. VPAC receptors were analyzed by real-time PCR and immunofluorescence, and CD4+CD28− T cells showed higher expression of VPAC2 and lower of VPAC1, VPAC2 showing a significant increased expression in EA cells. Sorted CD4+CD28− T cells were in vitro expanded in presence of VIP, wherein VIP increased senescent biomarker CD27, while it diminished CD57 or NKG2 senescent biomarkers. Our study demonstrates for the first time the existence of a link between senescent Th cells and the VIP axis.

Highlights

IntroductionSenescence profile of CD4 T cells, crucial cells in the development and functioning of immune response, is characterized by an expression loss of costimulatory molecules CD27 and CD28
Immunosenescence includes a number of functional changes in the immune system traditionally derived from cellular aging, which cause a near-constant state of inflammation, decreased immunity against pathogens, deficient responses to vaccines, and an increased risk of autoimmunity [1,2].Cells 2020, 9, 2592; doi:10.3390/cells9122592 www.mdpi.com/journal/cellsSenescence profile of CD4 T cells, crucial cells in the development and functioning of immune response, is characterized by an expression loss of costimulatory molecules CD27 and CD28
Patients who meet classification criteria for rheumatoid arthritis (RA) have a percentage of CD4+ CD28− higher than those with undifferentiated arthritis

Summary

Introduction

Senescence profile of CD4 T cells, crucial cells in the development and functioning of immune response, is characterized by an expression loss of costimulatory molecules CD27 and CD28 This phenotypic hallmark is accompanied with accumulation of regulatory T cells (Treg), severe proliferation impairment, a decline of telomerase activity, with the subsequent shortening of the telomere length, and the rise of natural killer (NK) surface molecules like CD57 or inhibitory receptors like PD-1 [3,4]. CD4+ CD28− T cells were first identified and characterized in patients with RA, where its frequency is positively correlated with advanced joint destruction and the development of extraarticular manifestations [8,9,10] In this sense, some authors considered these cells as a prognostic marker of radiographic progression in early arthritis (EA) [8].

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