γδ T Cells in Asthma

In this issue of Annals, Spinozzi and colleagues [1] report their observations on γδ T cells in the lungs of asthmatic patients. This is the first report of increased γδ T cells in the bronchoalveolar fluid from patients with asthma. Although they did not detect any γδ T cells in samples from the lungs of their controls or from patients with sarcoidosis, extrinsic allergic alveolitis, cystic fibrosis, or anatomic malformations of the airways, the finding of increased γδ T cells in the blood or in lung samples in patients with sarcoidosis and extrinsic allergic alveolitis has been previously reported [2-4]. Nevertheless, the finding of increased T cells in patients with asthma raises questions about the nature of these cells and their potential role in asthma.

T cells are a class of lymphocytes that undergo differentiation in the thymus and are the major regulatory cells of the immune system. They can secrete various cytokines that are important for both cellular and humoral responses. T cells can now be divided into two distinct populations on the basis of the T-cell antigen receptor (that is, α β or γδ) that they express. γδ T cells are a lineage of relatively recently discovered T cells that have many characteristics in common with the more prevalent α β T cells [5]. The two protein chains that make up this receptor complex consist of DNA segments of variable, diversity, junction, and constant regions that undergo recombination and expression in the thymus. During fetal thymic development, this process usually occurs for the γδ T cells before a similar process occurs for α β T cells [6].

In rodents, γδ T cells reside primarily in lymphoid tissues and in epithelia-rich tissues such as the skin and gut. In humans, an epithelial trophism is not found and most of these cells reside in the peripheral blood. γδ T cells share many of the effector functions of α β T cells, including cytokine production, cytotoxicity, and B-cell help. In patients with viral, bacterial, and parasitic infections, the numbers of γδ T cells have been shown to be increased at the site of the infection and may also be involved in the immune response against lung carcinomas [7].

In humans, most peripheral blood γδ T cells express antigen receptors encoded by a single γ- and δ-variable gene (Vγ9/Vδ2). The reason for this bias in receptor repertoire is uncertain, but it may be a consequence of bias in the recombination of individual gene segments or expansion of this population in response to various environmental pathogens. Vγ9/Vδ2 T cells have been shown to be reactive with various bacterial antigens—in particular, those of Mycobacterium tuberculosis[8].

Despite the structural similarity of antigen receptors expressed by γδ T and α β T cells, the manner in which the cells recognize antigen differs. α β T cells recognize antigen that has been processed or digested into peptides between 8 and 20 amino acids in length [9, 10]. These peptides are bound by HLA class I or class II molecules on the surface of antigen-presenting cells (B cells, macrophages, or dendritic cells) and presented to the α T-cell receptor. CD4 and CD8 molecules on the surface of the T cells determine whether a specific α β T cell will identify a peptide bound to a class I or class II molecule. In addition, a group of antigens known as superantigens bind to HLA class II molecules and to a particular V region of the T-cell antigen receptor.

In contrast, although various antigens are known to stimulate γδ T cells, the mechanisms by which these antigens stimulate these cells is not known [11]. Only a minority of γδ T cells appear to use classic HLA class I or class II molecules for the presentation of antigen. In addition, although specific superantigenic-type stimulation has been observed for γδ T cells, this stimulation appears to be independent of HLA class II molecules [12]. Structural analysis of γδ T-cell antigen receptor has suggested that it more closely resembles immunoglobulin than the α β T-cell antigen receptor, which is consistent with reported accounts of recognition of soluble antigens or antigens merely immobilized to tissue culture plastic by γδ T cells. Finally, although α β T cells appear to respond almost exclusively to small peptide antigens, γδ T cells may respond to various protein and nonprotein antigens.

Animal models of infectious diseases have clearly shown γδ T cells to have an important role in the clearance of infections [13-15]. Studies in α β T cell-deficient animals have also shown that although γδ T cells alone cannot protect against infection or disease by pathogenic organisms, they do appear to be required for the generation of efficient and effective immune responses. It has been proposed that γδ T cells have an immunoregulatory function in initiating and regulating the progression or resolution of inflammatory immune responses [13]. The long-proposed immune surveillance role of γδ T cells in the epithelial or mucosal tissues of rodents is also consistent with an immunoregulatory function of γδ T cells. However, because increased numbers of γδ T cells are not normally found in the lung or the gut, the role of γδ T cells in humans remains an enigma.

In light of this, the finding of Spinozzi and colleagues [1] of increased γδ T cells in the lungs of asthmatic patients is intriguing. Are these cells just passive bystanders recruited by the cytokine milieu present in the lungs of asthmatic patients, or are they responding to a particular antigenic stimulus and playing a role in the allergic response in asthma? Unfortunately, the appearance of these cells during active disease and their absence after treatment does not fully answer the question. In light of other studies that show responses of cloned γδ T cells to Dermatophagoides pteronyssinus[16], the presence of a proliferative response of the bronchoalveolar cells to the allergen D. pteronyssinus suggests that γδ T cells are immunopathologically important. However, McMenamin and colleagues [17] have recently reported that CD8⁺ γδ T cells in mice can specifically downregulate IgE responses to soluble ovalbumin. Thus, it remains unclear whether the regulatory role of γδ T cells in asthma is beneficial or harmful? In any case, together, these reports strongly suggest that γδ T cells play an important part in at least some asthmatic patients. The functional role of γδ T cells in asthma will undoubtedly be explored in more detail in the years to come and could result in new therapeutic initiatives.

• Copyright ©2004 by the American College of Physicians