Cytotoxic T-lymphocyte antigen 4 (CTLA4) is an important suppressor of T-cell–mediated immune responses and has become a major target in tumor therapy (1). Intriguingly, various case reports on initiation or exacerbation of sarcoidosis during anti-CTLA4 treatment of metastatic melanoma have recently emerged. This phenomenon is considered biotherapy-induced sarcoidosis, as in all reported cases, granuloma lesions occurred and progressed during biotherapy employment and disappeared after drug discontinuation (2). In patients with metastatic melanoma, CTLA4 blockade increased circulating proportions and absolute numbers of IL-17–producing CD4 1 T cells, whereas it only marginally changed Th1 or Th2 cell percentages (3). Although the effect on regulatory T cell (Treg) proportions remains a matter of debate, CTLA4 blockade was found to impair Treg-mediated suppression (1). Moreover, in both mice and humans, CTLA4 deletion, blockade, or dysfunction is strongly associated with the development of autoimmune lesions (1), in which Tregs and Th17 cells are known to play a pivotal role. Because sarcoidosis is characterized by an abnormal Th1/Th17 cell response and impaired Treg function (4), it is conceivable that CTLA4 blockade exacerbates underlying or preexistent disease. These clinical observations provide a rationale to examine CTLA4 expression on CD4 1 T cells in sarcoidosis in lung-draining mediastinal lymph nodes (MLN), which are an important site of primary and memory T-cell activation by dendritic cells. We hypothesize that altered CTLA4 expression contributes to ongoing Th1/Th17 cell responses in sarcoidosis. Using flow cytometry, we determined CTLA4 expression on CD4 1 T-cell subsets (for gating strategy, see Figure E1 in the online supplement) in MLN from patients with sarcoidosis (n= 18) and controls (n= 24)(for methods, see MATERIALS AND METHODS in the online supplement and Table E1).

Activated T cells from sarcoidosis MLN showed decreased CTLA4 expression compared with control MLN (Figure 1A). CTLA4 expression was also decreased on nonactivated memory T cells but normal on naive T cells (Figure E2). Evaluating Th cell subsets showed a significant decrease in CTLA4 expression specifically on sarcoidosis Th17 cells (P= 0.004) but not on Th1 or Th2 cells (Figures 1B and 1C). Furthermore, proportions of Th17 cells were significantly increased in sarcoidosis MLN (Figure 1D), consistent with our previous finding of enhanced Th17 cell proportions in peripheral blood and lungs of patients (5).