The PI-3-Kinase P110α Catalytic Subunit of T Lymphocytes Modulates Collagen-Induced Arthritis.

María Montes-Casado,Gabriel Criado,Pilar Portolés,José M Rojo,Gloria Ojeda

doi:10.3390/ijms22126405

Abstract

The phosphatidylinositol 3-kinase (PI3K) family of enzymes plays a determinant role in inflammation and autoimmune responses. However, the implication of the different isoforms of catalytic subunits in these processes is not clear. Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disease that entails innate and adaptive immune response elements in which PI3K is a potential hub for immune modulation. In a mouse transgenic model with T-cell-specific deletion of p110α catalytic chain (p110α−/−ΔT), we show the modulation of collagen-induced arthritis (CIA) by this isoform of PI3K. In established arthritis, p110α−/−ΔT mice show decreased prevalence of illness than their control siblings, higher IgG1 titers and lower levels of IL-6 in serum, together with decreased ex vivo Collagen II (CII)-induced proliferation, IL-17A secretion and proportion of naive T cells in the lymph nodes. In a pre-arthritis phase, at 13 days post-Ag, T-cell-specific deletion of p110α chain induced an increased, less pathogenic IgG1/IgG2a antibodies ratio; changes in the fraction of naive and effector CD4+ subpopulations; and an increased number of CXCR5+ T cells in the draining lymph nodes of the p110α−/−ΔT mice. Strikingly, T-cell blasts in vitro obtained from non-immunized p110α−/−ΔT mice showed an increased expression of CXCR5, CD44 and ICOS surface markers and defective ICOS-induced signaling towards Akt phosphorylation. These results, plus the accumulation of cells in the lymph nodes in the early phase of the process, could explain the diminished illness incidence and prevalence in the p110α−/−ΔT mice and suggests a modulation of CIA by the p110α catalytic chain of PI3K, opening new avenues of intervention in T-cell-directed therapies to autoimmune diseases.

Highlights

Rheumatoid arthritis is a chronic, systemic autoimmune inflammatory disease that primarily affects the joints and that is characterized by progressive destruction of articular structures, causing articular pain, inflammation, stiffness and loss of function
We considered whether the higher number of cells observed in p110α− / − ∆T mice in pre-arthritis stage could be due to an increased expression of homing surface markers, such as CXCR5 and CD44, in activated T cells of p110α− / − ∆T mice
When intracellular signaling was analyzed we found a decrease in the phosphoinositide-3 kinases (PI3K)-dependent phosphorylation of Akt induced by ICOS alone or when ICOS acts as a TCR-co-stimulus in the p110α− / − ∆T blasts (Figure 7D)

Summary

Introduction

Rheumatoid arthritis is a chronic, systemic autoimmune inflammatory disease that primarily affects the joints and that is characterized by progressive destruction of articular structures, causing articular pain, inflammation, stiffness and loss of function. As an autoimmune disease, yet unknown environmental challenges activate innate immune-response elements, providing an adjuvant signal for the induction of adaptive immune responses dependent on CD4+ helper T cells. This leads to the production of antibodies specific for joint self-antigens producing an inflammatory reaction [2,4]. All of these processes should be sensitive to inhibitors of steps essential to the development of adaptive immune responses, including antigen recognition and activation, or costimulatory, cytokine or chemokine signaling [4]. Class I PI3K recruiting and activation is a hallmark of antigen recognition and of signaling by T (CD28, ICOS) and B (CD19) costimulatory molecules

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