title: Reversal of global CD4+ subset dysfunction is associated with spontaneous clinical resolution of pulmonary sarcoidosis.
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.
authors: Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. kyra.richter@vanderbilt.edu
authors: Kyra A
authors: KA
authors: Oswald-Richter
authors: Bradley W
authors: BW
authors: Richmond
authors: Nicole A
authors: NA
authors: Braun
authors: Joan
authors: J
authors: Isom
authors: Susamma
authors: S
authors: Abraham
authors: Thyneice R
authors: TR
authors: Taylor
authors: John M
authors: JM
authors: Drake
authors: Daniel A
authors: DA
authors: Culver
authors: David S
authors: DS
authors: Wilkes
authors: Wonder P
authors: WP
authors: Drake
mesh_terms: D000328:Adult; D000368:Aged; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D017635:Clonal Anergy / Q000276:immunology; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D012075:Remission, Spontaneous; D017565:Sarcoidosis, Pulmonary / Q000276:immunology*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
chemical_list: D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell
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