The Role of Gamma Delta T Cells in Autoimmune Rheumatic Diseases

Abstract

Autoimmune rheumatic diseases (ARDs), affecting ~1-1.5% of all humans, are associated with considerable life long morbidity and early mortality. Early studies in the 1990s showed numerical changes of the recently discovered γδ T cells in the peripheral blood and in affected tissues of patients with a variety of ARDs, kindling interest in their role in the immuno-pathogenesis of these chronic inflammatory conditions. Indeed, later studies applied rapid developments in the understanding of γδ T cell biology, including antigens recognized by γδ T cells, their developmental programs, states of activation, and cytokine production profiles, to analyze their contribution to the pathological immune response in these disorders. Here we review the published studies addressing the role of γδ T in the major autoimmune rheumatic diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, systemic lupus erythematosus and scleroderma, and animal models thereof. Due to their unique properties spanning adaptive and innate immune functions, the ever deeper understanding of this unique T cell population is shedding new light on the pathogenesis of, while potentially enabling new therapeutic approaches to, these diseases.

Keywords: ankylosing spondylitis; gammadelta T cells; juvenile idiopathic arthritis; rheumatoid arthritis; systemic lupus erythematosus; systemic sclerosis.

Figure 1

Participation of γδ T cells in Rheumatoid Arthritis. Vδ1⁺ γδ T cells using Vγ3, Vγ8 or other Vγ genes, recognize antigens presented by CD1d or MR1 on synovial fibroblasts, and/or antigens presented by antigen presenting cells, and secrete cytokines such as interleukin (IL)-17, IL-4, and IFNγ [27,37,38,40,41,48]. Chemokines produced in inflamed synovium, attract C-X-C motif chemokine receptor (CXCR)5 and C-C motif chemokine receptor (CCR)3 expressing Vγ9⁺ T cells to the synovium [27]. These cells are activated by phosphoantigens presented by CD277 expressing cells in the synovium to express human leukocyte antigen (HLA)-DR, and in turn, may present antigens to CD4⁺ αβ T cells [24]. Vδ1⁻Vδ2⁻ γδ T cells recognizing unknown antigens also participate in the synovial reaction [35]. IL-17 secreted by CD4⁺ αβ T cells activated by Vγ9⁺ γδ T cells may attract neutrophils and lead to osteoclastogenesis. In the presence of anti tumor necrosis factor (TNF)α antibodies, chemokines retaining the Vγ9⁺ T cells are decreased, and these cells migrate out of the joint to the peripheral blood. Peripheral blood γδ T cells express activation markers acquired in lymph nodes or as a reflection of activation in the synovium [24,25,28].

Figure 2

Hypothetical model incorporating the immunopathogenetic role of γδ T cells in human systemic lupus erythematosus (SLE) and murine models. γδ T cells may become activated by plasmacytoid dendritic cells pDC in lymph nodes, leading to their secretion of proinflammatory cytokines such as IL-17 and IFNγ, an activity modulated by BLK [93]. A subset of γδ T cells expressing CXCR5 release Wingless-related integration site (Wnt) proteins, that enhance differentiation of naïve T cells to become follicular helper T cells [100], which in turn, together with IL-4 secretion [97] differentiate B cells to become antigen producing cells making anti DNA antibodies. Other γδ T cells directly interact with heat shock protein (HSP)65 expressing B cells via their T cell receptor (TCR) and help drive anti DNA antibody secretion [92]. At the same time regulatory FoxP3⁺ γδ T cells may become activated by transforming growth factor (TGF)β produced by pDC [18], and by CD1d expressing cells in a TCR dependent manner, to downregulate the immune response [99]. After activation in lymph nodes, γδ T cells could migrate to the kidney where they secrete IL-17, thus enhancing migration of leukocytes [101].

Figure 3

Role of γδ T cells in human systemic sclerosis. On the right, representing patients without interstitial lung disease, are, cytotoxic granzyme expressing Vδ2⁺ γδ T cells in the peripheral blood, which are shown to interact with the endothelium via engagement of the TCR with CD277 endothelial molecules activated by isopentenyl pyrophosphate (IPP), while inducing the procoagulant tissue factor on monocytes, which together could lead to endothelial damage [103,107]. The peripheral blood is enriched in CD161⁺Vδ1⁺ T cells [104]. Profibrotic Vδ1⁺ cells may migrate to the lung, where they encounter cells expressing CD1d in complex with lipids, which trigger Vδ1⁺ T cells to secrete profibrotic factors (e.g., IL-4, CCL3) [104,105,110]. Along with this, exit of Vδ2⁺ T cells (which may potentially confer anti fibrotic functions), from the lung to the peripheral blood takes place [106,111]. These alterations of γδ T cell composition in the lung may contribute to progressive lung disease.