Immune-Checkpoint Expression on CD4, CD8 and NK Cells in Blood, Bronchoalveolar Lavage and Lymph Nodes of Sarcoidosis

Abstract

Background Sarcoidosis features non-necrotizing granulomas consisting mainly of activated CD4-lymphocytes. T-cell activation is regulated by immune checkpoint (IC) molecules. The present study aimed to compare IC expression on CD4, CD8 and NK cells from peripheral, alveolar and lung-draining lymph node (LLN) samples of sarcoidosis patients. Methods Flow-cytometry analysis was performed to detect IC molecules and a regression decision tree model was constructed to investigate potential binary classifiers for sarcoidosis diagnosis as well as for the IC distribution. Results Fourteen patients (7 females) were consecutively recruited in the study; all enrolled patients showed hilo-mediastinal lymph node enlargement and lung parenchyma involvement with chest X-rays and high resolution computed tomography. CD4+PD1+ and CD8+PD1+ were higher in bronchoalveolar lavage (BAL) than in LLN (p = 0.0159 and p = 0.0439, respectively). CD4+ T-cell immunoglobulin and ITIM domain (TIGIT)+ were higher in BAL than in peripheral blood mononuclear cells (PBMCs) (p = 0.0239), while CD8+TIGIT+ were higher in PBMC than in BAL (p = 0.0386). CD56+TIGIT+ were higher in LLN than in PBMC (p = 0.0126). The decision-tree model showed the best clustering cells of PBMC, BAL and LLN: CD56, CD4/CD8 and CD4+TIGIT+ cells. Considering patients and controls, the best subset was CD4+CTLA-4+. Conclusion High expression of PD1 and TIGIT on T cells in BAL, as well as CTLA-4 and TIGIT on T cells in LLN, suggest that inhibition of these molecules could be a therapeutic strategy for avoiding the development of chronic inflammation and tissue damage in sarcoidosis patients. Miriana d'Alessandro & Laura Bergantini contributed equally to the study.

Imbalance of Lymphocyte Subsets and CD45RA-Expressing Cells in Intrathoracic Lymph Nodes, Alveolar Compartment and Bloodstream of Pulmonary Sarcoidosis Patients

“…This eventually leads to their migration to inflammatory foci and the formation of granulomas [ 20 ]. The present study confirmed data in the literature on depletion of CD56 dim 16 bright and CD8 + T cells in LLN and BAL samples with respect to PB, suggesting that these cells play a protective role in sarcoidosis [ 5 , 17 ].…”

“…Sarcoid lung involvement can be evaluated by flexible bronchoscopy with bronchoalveolar lavage (BAL), cytological analysis and evaluation of T cell expression, typically characterized by an increase in alveolar lymphocytes having an elevated CD4/CD8 ratio [ 4 ]. For better diagnostic accuracy, it is advisable to perform endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) during flexible bronchoscopy, a minimally invasive technique that allows sampling of lung-draining lymph nodes (LLNs) for cytological analysis [ 5 , 6 ]. This procedure has been widely adopted and is currently recommended by international guidelines as the gold standard for evaluating intrathoracic lymphadenopathy in cases of suspected sarcoidosis [ 7 ].…”

Immune checkpoint analysis of T‐cell responses to pp65 and IE‐1 antigens in end‐stage lung diseases

“…13,15 Programmed cell death 1 (PD-1), cytotoxic Tlymphocyte antigen 4 (CTLA-4) and lymphocyte activation gene 3 (LAG-3) are inhibitory receptors associated with the exhaustion phenotype of T cell. 16 Recently, T immunoreceptor with immunoglobulin and ITIM domain (TIGIT), a new molecules with immunoregulatory properties, has been discovered. It is considered a promising new target for cancer immunotherapy.…”

Evaluation of PD-1 T lymphocytes in bronchoalveolar lavage in lung cancer compared to benign lung diseases

“…While there is limited data on PD-1 + T cells in lung cancer, there is even less knowledge regarding PD-1 expression on T cells in patients with benign lung diseases. d'Alessandro and colleagues reported a high expression of PD-1 on T cells in BAL of patients with sarcoidosis [ 12 ]. Kronborg-White et al described an expression of PD-L1 in epithelial cells in a subgroup of patients with IPF [ 13 ].…”