Memory T Cells in the Chronic Inflammatory Microenvironment of Nasal Polyposis are Hyporesponsive to Signaling Through the T Cell Receptor

Abstract

A majority of T cells from chronic inflammatory tissues derived from patients with nasal polyposis were found to express an effector memory phenotype. We report here that these memory T cells failed to activate NF-κB in response to TCR stimulation but responded normally when the proximal TCR signaling molecules were bypassed with PMA and ionomycin. The dysfunction of these cells was associated with a decrease in the phosphorylation of several TCR proximal signaling molecules including ZAP70, Lck and SLP-76. In addition to the disruption in the TCR signaling pathway, the nasal polyp-associated T cells were shown to have a defect in their ability to translocate LAMP-1 to the cell surface. The results presented here establish that the phenotype and anergy of the T cells in the nasal polyp are similar to those which is seen in memory T cells derived from human tumors and other sites of chronic inflammation.

Exosomes Represent an Immune Suppressive T Cell Checkpoint in Human Chronic Inflammatory Microenvironments

“…Subsequent studies showed that the CD3+ T cells in polyps are predominantly CD8+ with a minority of CD4+ T cells (Bernstein et al, 2004;Ickrath et al, 2017), and that the majority of these CD8+ T cells express CD44, CD45RO, CD28, and CXCR3 and are negative for CD62L and CD25 (Baba et al, 2015;Lehman et al, 2012;Pant et al, 2013;Sanchez-Segura et al, 1998). This phenotype is consistent with that of T cells called effector memory T cells, (T EM ) (Sallusto et al, 1999).…”

“…However, when T-cells derived from nasal polyps were tested for their response to activation via the T-cell receptor, it was established that both CD4+ and CD8+ T-cells were profoundly hypo-responsive to an activation stimulus (Lehman et al, 2012). These T-cells had a phenotype of effector memory cells and their anergy was manifested by a blockade in the activation signaling cascade before or just after diacylglycerol (Lehman et al, 2012).…”

“…However, when T-cells derived from nasal polyps were tested for their response to activation via the T-cell receptor, it was established that both CD4+ and CD8+ T-cells were profoundly hypo-responsive to an activation stimulus (Lehman et al, 2012). These T-cells had a phenotype of effector memory cells and their anergy was manifested by a blockade in the activation signaling cascade before or just after diacylglycerol (Lehman et al, 2012). Similar hypo-responsiveness has now been demonstrated in the T-cells derived from the chronic inflammatory microenvironments of tumor tissues and this T cell arrest was postulated to result from the phosphorylation of diacylglycerol into an inactive phosphatidic acid by diacylglycerol kinase (Kelleher et al, 2015).…”

“…This led investigators to determine whether the T EM from nasal polyps are similarly impaired in their ability to be activated. T cells derived from multiple different nasal polyp tissues were found to be hyporesponsive to activation while T cells derived from the peripheral blood of the nasal polyp patients responded normally to the same stimulation (Lehman et al, 2012).…”

Gearing up for the Future: Mitigating Dysregulated Inflammation in Aging and Facets of Obesity

“…Moreover, as the VAT environment is hypoxic and rich in FFA, it promotes the activation of VAT-infiltrating macrophages via the HIF-1α and TLR4 signalling pathways, leading to the production of TNFα and further establishing a pro-inflammatory environment [35][36][37][38]. These multiple factors could work in concert to overwhelm the anti-inflammatory cytokines and environment produced by TH2 CD4 T cells, iNKT and Treg cells [39][40][41][42][43][44][45].…”