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

Oswald-Richter KA, Richmond BW, Braun NA, Isom J, Abraham S, Taylor TR, Drake JM, Culver DA, Wilkes DS, Drake WP
J Immunol. 2013 190 (11): 5446-53

PMID: 23630356 · PMCID: PMC3660530 · DOI:10.4049/jimmunol.1202891

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.

MeSH Terms (18)

Adult Aged Bronchoalveolar Lavage Fluid CD4-Positive T-Lymphocytes Clonal Anergy Female Humans Interleukin-2 Male Middle Aged Receptors, Antigen, T-Cell Remission, Spontaneous Sarcoidosis, Pulmonary Signal Transduction T-Lymphocytes, Helper-Inducer T-Lymphocytes, Regulatory T-Lymphocyte Subsets Young Adult

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