Local and Systemic CD4⁺ T Cell Exhaustion Reverses with Clinical Resolution of Pulmonary Sarcoidosis

Abstract

Investigation of the Th1 immune response in sarcoidosis CD4+ T cells has revealed reduced proliferative capacity and cytokine expression upon TCR stimulation. In other disease models, such cellular dysfunction has been associated with a step-wise, progressive loss of T cell function that results from chronic antigenic stimulation. T cell exhaustion is defined by decreased cytokine production upon TCR activation, decreased proliferation, increased expression of inhibitory cell surface receptors, and increased susceptibility to apoptosis. We characterized sarcoidosis CD4+ T cell immune function in systemic and local environments among subjects undergoing disease progression compared to those experiencing disease resolution. Spontaneous and TCR-stimulated Th1 cytokine expression and proliferation assays were performed in 53 sarcoidosis subjects and 30 healthy controls. PD-1 expression and apoptosis were assessed by flow cytometry. Compared to healthy controls, sarcoidosis CD4+ T cells demonstrated reductions in Th1 cytokine expression, proliferative capacity (p < 0.05), enhanced apoptosis (p < 0.01), and increased PD-1 expression (p < 0.001). BAL-derived CD4+ T cells also demonstrated multiple facets of T cell exhaustion (p < 0.05). Reversal of CD4+ T cell exhaustion was observed in subjects undergoing spontaneous resolution (p < 0.05). Sarcoidosis CD4+ T cells exhibit loss of cellular function during progressive disease that follows the archetype of T cell exhaustion.

Expression of PD-1 on CD4+Tumor-Infiltrating Lymphocytes in Tumor Microenvironment Associated with Pathological Characteristics of Breast Cancer

“…CD4 + /PD-1 + T lymphocytes were found to be in close contact with PD-L1 + chronic lymphocytic leukemia cells [ 19 ] and the activated PD-1/PD-L1 axis led to decreased production of IL-4 from CD4 + T lymphocytes [ 19 ]. High level of CD4 + /PD1 + lymphocytes, reduced cytokine secretion, dysfunctional proliferation, and increased apoptosis were also observed among sarcoidosis patents [ 20 , 21 ], but blocking PD-1 pathway in CD4 + T cells could reverse the proliferative capacity [ 21 ]. The expression of PD-1 on CD4 + lymphocytes indicated exhausted function [ 20 , 21 ].…”

“…High level of CD4 + /PD1 + lymphocytes, reduced cytokine secretion, dysfunctional proliferation, and increased apoptosis were also observed among sarcoidosis patents [ 20 , 21 ], but blocking PD-1 pathway in CD4 + T cells could reverse the proliferative capacity [ 21 ]. The expression of PD-1 on CD4 + lymphocytes indicated exhausted function [ 20 , 21 ]. CD4 + /PD1 + TILs were dysfunctional in the presence of PD-L1 among patients with head and neck squamous cell carcinomas [ 22 ] and glioblastoma multiforme (GBM) [ 5 ].…”

Clinical Presentations, Pathogenesis, and Therapy of Sarcoidosis: State of the Art

“…Pulmonary CD4+ T cells from patients with sarcoidosis spontaneously secrete IL-2 ex vivo, but upon TCR stimulation, they express less IL-2 and IFN-γ compared to CD4+ T cells from other lung diseases and healthy controls, in line with an anergic/exhausted phenotype [60]. Other signs of Th1 anergy/exhaustion due to prolonged antigen exposure in sarcoidosis are their reduced proliferative capacity and their higher levels of apoptosis, associated with increased programmed death (PD)-1 expression [61].…”

Adaptive Immunity in Pulmonary Sarcoidosis and Chronic Beryllium Disease

“…Pulmonary CD4+ T cells from sarcoidosis spontaneously secrete IL-2 ex vivo, but when given TCR stimulation, these cells express less IL-2 and IFN-γ relative to CD4+ T cells from various other lung diseases and healthy control subjects, consistent with an anergic/exhausted phenotype (58). Additionally, sarcoidosis CD4+ T cells have a reduced proliferative capacity and higher levels of apoptosis, along with increased PD-1 expression, which is often associated with persistent antigen exposure to limit chronic T cell activation (59,60). A recent study demonstrated that PD-1 expression was highest on sarcoidosis CD4+ T cells with a Th17 phenotype (61).…”