Lymphocyte senescence in COPD is associated with decreased histone deacetylase 2 expression by pro-inflammatory lymphocytes

3.2 Airway Cell Biology and Immunopathology

Jersmann

Tran

et al. 2016

Self Cite

Background: Corticosteroid resistance is a major barrier to effective treatment of COPD. We have shown that the resistance is associated with decreased expression of glucocorticoid receptor (GCR) by senescent CD28nullCD8+ pro-inflammatory lymphocytes in peripheral blood of COPD patients. GCR must be bound to molecular chaperones heat shock proteins (Hsp) 70 and Hsp90 to acquire a high-affinity steroid binding conformation, and traffic to the nucleus. We hypothesized a loss of Hsp70/90 from these lymphocytes may further contribute to steroid resistance in COPD.

Section: Increased Cd28null Cd8+ T and Nkt-like Cells In Copd Patientssupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Steroid resistance in COPD is associated with impaired molecular chaperone HSP90 expression by pro-inflammatory lymphocytes

3.2 Airway Cell Biology and Immunopathology

Jersmann

Tran

et al. 2016

Self Cite

“…In this regard, the glucocorticoid receptor (GCR) has recently been shown to be decreased in pro‐inflammatory T and NKT‐like cells post‐lung transplant which may help to explain steroid resistance following lung transplant . Interestingly, HDAC2 has been shown to be decreased in macrophages in COPD and recently in lymphocytes, another progressive chronic inflammatory lung disease also shown to be associated with increased cytotoxic pro‐inflammatory T and NKT‐like cells similar to our findings for lung transplant patients …”

Section: Introductionmentioning

confidence: 99%

Histone deacetylase 2 is decreased in peripheral blood pro‐inflammatory CD8+ T and NKT‐like lymphocytes following lung transplant

Holmes‐Liew

et al. 2016

Respirology

Self Cite

“…HDAC2 is required by corticosteroids to switch off activated inflammatory genes and is reduced in lung macrophages in COPD (10). A recent study showed that HDAC2 expression was suppressed in pro-inflammatory CD8 + CD28 null NKT-like cells in patients with COPD (19) and negatively correlated with the percentage of CD8 + CD28 null NKT-like cells producing IFNγ or TNFα in all subjects (e.g., COPD: R = −0.789, p < 0.001 for CD8 + CD28 null NKT-like cells producing IFNγ) (Figure 2D). Theophylline is an activator of HDAC and enhances the anti-inflammatory effects of corticosteroids in alveolar macrophages in COPD patients (20).…”

Section: Steroid Resistance In Cd8+cd28null Nkt-like Cells In Copdmentioning

confidence: 83%

Steroid Resistant CD8+CD28null NKT-Like Pro-inflammatory Cytotoxic Cells in Chronic Obstructive Pulmonary Disease

2016

Front. Immunol.

Self Cite

Corticosteroid resistance is a major barrier to effective treatment in chronic obstructive pulmonary disease (COPD), and failure to suppress systemic inflammation in these patients may result in increased comorbidity. Although much of the research to date has focused on the role of macrophages and neutrophils involved in inflammation in the airways in COPD, recent evidence suggests that CD8+ T cells may be central regulators of the inflammatory network in this disease. CD8+ cytotoxic pro-inflammatory T cells have been shown to be increased in the peripheral blood and airways in patients with COPD, whereas smokers that have not progressed to COPD only show an increase in the lungs. Although the mechanisms underlying steroid resistance in these lymphocytes is largely unknown, new research has identified a role for cytotoxic pro-inflammatory CD8+ T-cells and CD8+ natural killer T-like (NKT-like) cells. Increased numbers of these cells and their significant loss of the co-stimulatory molecule CD28 have been shown in COPD, consistent with findings in the elderly and in clinical conditions involving chronic activation of the immune system. In COPD, these senescent cells expressed increased levels of the cytotoxic mediators, perforin and granzyme b, and the pro-inflammatory cytokines, IFNγ and TNFα. They also demonstrated increased cytotoxicity toward lung epithelial cells and importantly were resistant to immunosuppression by corticosteroids compared with their CD28+ counterparts. Further research has shown these cells evade the immunosuppressive effects of steroids via multiple mechanisms. This mini review will focus on cytotoxic pro-inflammatory CD8+CD28null NKT-like cells involved in COPD and novel approaches to reverse steroid resistance in these cells.