Regulatory T cells (red), shown in a sarcoidosis granuloma, inhibit T cell proliferation, but not their cytokine production.

Sarcoidosis is a mysterious, long-recognized disease characterized by the formation of tuberculosis-like granulomas in the lungs. The mystery of sarcoidosis stems from both its unknown etiology and its paradoxical effects on the immune system. The disease has been attributed to a hyperactivation of CD4+ T helper type 1 cells that infiltrate the lungs but, in patients with sarcoidosis, these very cells fail to proliferate in response to recall antigens.

On page 359, Miyara and colleagues suggest that half-cocked regulatory T (T reg) cells that inhibit proliferation by T cells but not their cytokine production might be to blame for this immune contradiction.

T reg cells normally help suppress chronic inflammation by inhibiting both effector T cell proliferation and cytokine production. Miyara et al. now show that although T reg cell numbers are elevated in both the blood and the lungs of patients with sarcoidosis, these cells were unable to curb the CD4+ T cell production of TNF and interferon (IFN)-γ—inflammatory cytokines that drive the formation and maintenance of granulomas. However, the patients' T reg cells could still shut down effector T cell proliferation, possibly explaining the inability of T cells to respond to recall antigens.

The mechanism behind the T reg cell defect in patients with sarcoidosis remains to be defined, but might be a byproduct of chronic inflammation, as half-active T reg cells have also been found in autoimmune inflammatory diseases such as rheumatoid arthritis and multiple sclerosis.