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 (<i>p</i> < 0.05), enhanced apoptosis (<i>p</i> < 0.01), and increased PD-1 expression (<i>p</i> < 0.001). BAL-derived CD4⁺ T cells also demonstrated multiple facets of T cell exhaustion (<i>p</i> < 0.05). Reversal of CD4⁺ T cell exhaustion was observed in subjects undergoing spontaneous resolution (<i>p</i> < 0.05). Sarcoidosis CD4⁺ T cells exhibit loss of cellular function during progressive disease that follows the archetype of T cell exhaustion.