Reversal of global CD4+ subset dysfunction is associated with spontaneous clinical resolution of pulmonary sarcoidosis

Kyra A. Oswald-Richter, Bradley W. Richmond, Nicole A. Braun, Joan Isom, Susamma Abraham, Thyneice R. Taylor, John M. Drake, Daniel A. Culver, David S. Wilkes, Wonder P. Drake

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Sarcoidosis pathogenesis is characterized by peripheral anergy and an exaggerated, pulmonary CD4+ Th1 response. In this study, we demonstrate that CD4+ anergic responses to polyclonal TCR stimulation are present peripherally and within the lungs of sarcoid patients. Consistent with prior observations, spontaneous release of IL-2 was noted in sarcoidosis bronchoalveolar lavage CD4+ T cells. However, in contrast to spontaneous hyperactive responses reported previously, the cells displayed anergic responses to polyclonal TCR stimulation. The anergic responses correlated with diminished expression of the Src kinase Lck, protein kinase C-θ, and NF-κB, key mediators of IL-2 transcription. Although T regulatory (Treg) cells were increased in sarcoid patients, Treg depletion from the CD4+ T cell population of sarcoidosis patients did not rescue IL-2 and IFN-γ production, whereas restoration of the IL-2 signaling cascade, via protein kinase C-θ overexpression, did. Furthermore, sarcoidosis Treg cells displayed poor suppressive capacity indicating that T cell dysfunction was a global CD4+ manifestation. Analyses of patients with spontaneous clinical resolution revealed that restoration of CD4+ Th1 and Treg cell function was associated with resolution. Conversely, disease progression exhibited decreased Th1 cytokine secretion and proliferative capacity, and reduced Lck expression. These findings implicate normalized CD4+ T cell function as a potential therapeutic target for sarcoidosis resolution.

Original languageEnglish (US)
Pages (from-to)5446-5453
Number of pages8
JournalJournal of Immunology
Volume190
Issue number11
DOIs
StatePublished - Jun 1 2013

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Oswald-Richter, K. A., Richmond, B. W., Braun, N. A., Isom, J., Abraham, S., Taylor, T. R., Drake, J. M., Culver, D. A., Wilkes, D. S., & Drake, W. P. (2013). Reversal of global CD4+ subset dysfunction is associated with spontaneous clinical resolution of pulmonary sarcoidosis. Journal of Immunology, 190(11), 5446-5453. https://doi.org/10.4049/jimmunol.1202891