Role of CD4+ T cells in sarcoidosis

Abstract

Activated pulmonary CD4(+) T lymphocytes of the Th-1 type are essential for the inflammatory process in sarcoidosis, and IFN-gamma production is crucial for the characteristic granuloma formation. Both the T cells and their inflammatory mediators may constitute possible targets for immunotherapy. A particular T-cell subset, the T-cell receptor (TCR) AV2S3(+) bronchoalveolar lavage (BAL) CD4(+) T cells, is found at dramatically increased levels in the BAL fluid of human leukocyte antigen (HLA)-DRB1*0301-positive and/or HLA-DRB3*0101-positive patients with sarcoidosis. The AV2S3(+) BAL CD4(+) T cells strongly associate with the sarcoid inflammation, and future studies on this particular T-cell subset to reveal their specificity may lead to the identification of sarcoidosis-specific antigen(s). T-cell subpopulations with regulatory functions (i.e., natural killer T cells and T regulatory cells) have recently been described as abnormal in sarcoidosis. Dysfunctional regulatory T cells may allow T effector cells to contribute to the formation of granulomas, and they may thus be relevant for the inflammatory process in this disease. These findings are exciting news and will be of help in designing new treatment strategies.

Figure 1.

Unknown antigens are presented by antigen-presenting cells (APC) and recognized by CD4⁺ T helper cells (1). As a result, CD4⁺ T cells and macrophages are stimulated to proliferate and to produce inflammatory mediators, such as IL-2, IFN-γ, and tumor necrosis factor (TNF)-α (2), which are considered pivotal for granuloma formation (3). The granulomas consist of epithelioid macrophages, giant cells, and lymphocytes, which are mostly CD4⁺ T cells.

Figure 2.

Natural killer T (NKT) cells recognize glycolipids presented by CD1d molecules and are capable of producing large amounts of IFN-γ and IL-4. They are considered to have immunoregulatory effects. The reduced levels and/or dysfunctional NKT cells that have been described in sarcoidosis (12–14) may lead to a loss of control of the activated Th1 proinflammatory cells in sarcoidosis, theoretically through reduced NKT cell production of IL-4 (42), which has down-regulatory effects on Th1 cells. HLA = human leukocyte antigen.

Figure 3.

An antigen is processed by an antigen-presenting cell (APC) and presented in the form of a peptide in the context of an HLA molecule. According to our hypothesis, both HLA-DRB1*0301 and HLA-DRB3*0101 molecules can present identical peptides, and be recognized preferentially by T-cell receptor AV2S3⁺ CD4⁺ T lymphocytes. Ag = antigen.