Costimulatory Pathways in Rheumatoid Synovitis and T‐Cell Senescence

Abstract

The pathogenesis of rheumatoid arthritis (RA) is determined by a complex interaction of genetic and environmental factors. Of all risk factors, age has the largest impact. RA occurs most often during the postmenopausal period of life, with incidence rates peaking in the eighth decade. While age is generally accepted as an etiologic factor for failure of immunocompetence, much less is understood about the role of T-cell senescence in autoimmunity. We have hypothesized that senescent T cells are particularly prone to be activated in specialized microenvironments, such as the synovial membrane. CD4 T cells in the senescence program were identified by the loss of CD28. Gene expression profiling documented that CD28- T cells have acquired a spectrum of regulatory receptors that are usually seen only on NK cells. Such regulatory receptors include stimulatory and inhibitory members of the killer immunoglobulin-like receptor (KIR) family, the stimulatory c-type lectin receptor NKG2D, and CX3CR1, the receptor for the chemokine fractalkine. Synovial fibroblasts express the relevant ligands, thus providing stimulatory signals to tissue-infiltrating T cells. The signaling pathways of these regulatory receptors are complex and dependent on the individual T cells, some of which express important adapter molecules such as DAP10 and DAP12. Inhibitory KIRs on T cells are often only partially functional. Our data suggest that, by virtue of altered receptor profiles, conventional tolerance mechanisms can be evaded in the aging host. By acquiring a new set of regulatory receptors, senescent CD4 T cells become responsive to novel environmental cues and find ideal stimulatory conditions in the synovial microenvironment.

Cellular senescence impact on immune cell fate and function

“…Although CD4 + T cells are more resistant to age‐related phenotypic and functional changes than CD8 + T cells (Weinberger et al ., 2007), a progressive increase in the percentage of senescence‐like CD4 + T cells is common with increasing age in healthy individuals (Goronzy et al ., 2007; Czesnikiewicz‐Guzik et al ., 2008). This increase in senescence‐like CD4 + T cells is also observed in patients with chronic infections (Fletcher et al ., 2005) and autoimmune diseases such as rheumatoid arthritis (RA) (Goronzy et al ., 2005). Analysis of telomere length in the same healthy individual revealed that naïve CD4 + and CD8 + T cells have consistently longer telomeres than memory T cells at all ages, suggesting that the differentiation of naïve into memory T cells involves a relatively constant number of cell divisions independent of the donor's age (Weng et al ., 1998; Effros, 2011).…”

Unchecked CD70 Expression on T Cells Lowers Threshold for T Cell Activation in Rheumatoid Arthritis

“…Killer Ig-like receptor 2DS2 has been shown to be a genetic risk factor for extra-articular complications of RA (2,25). NKG2D is expressed on end-differentiated CD4 T cells and provides a costimulatory signal recognizing a ligand expressed in the synovial tissue (22,26). Similarly, fractalkine receptor is expressed on senescent CD4 T cells and communicates with synovial fibroblasts through the recognition of fractalkine (23).…”

Activating NK‐cell receptors co‐stimulate CD4+CD28− T cells in patients with rheumatoid arthritis

“…Activating receptors may fine-tune the thresholds for TCR signaling and potentiate the effector response of the T cells [15]. In RA, a significant proportion of CD4 1 CD28 À T cells were shown to express natural killer group 2D (NKG2D), which stimulated autoreactive responses against RA synoviocytes displaying anomalous expression of the NKG2D ligands MHC class I chainrelated protein (MIC)A and MICB [5,16]. Furthermore, expression of activating killer cell Ig-like receptors (KIR) on CD4 1 T cells has been associated with severe disease manifestations in RA patients [17].…”