T cells in rheumatoid arthritis

Abstract

Over the past decade and a half, advances in our understanding of the pathogenesis of immune-mediated diseases such as rheumatoid arthritis (RA) have translated directly into benefit for patients. Much of this benefit has arisen through the introduction of targeted biological therapies. At the same time, technological advances have made it possible to define, at the cellular and molecular levels, the key pathways that influence the initiation and persistence of chronic inflammatory autoimmune reactions. As our understanding grows, it is likely that this knowledge will be translated into a second generation of biological therapies that are tailor-made for the patient. This review summarizes current perspectives on RA disease pathogenesis, with particular emphasis on what RA T cells look like, what they are likely to see, and how they contribute to persistence of the chronic inflammatory response.

Figure 1

The phenotype of RA synovial T cells. The schematic depicts examples of cell surface antigens and receptors that confer distinct phenotypes according to antigen experience, differentiation, and acquisition of memory, migratory competence, terminal differentiation and immune senescence, and effector function. CCR, CC chemokine receptor; CX3CR, CX3C chemokine receptor; CXCR, CXC chemokine receptor; LFA, lymphocyte function-associated antigen; LT, lymphotoxin; mTNF, membrane-associated tumor necrosis factor; NK, natural killer; RA, rheumatoid arthritis; RANKL, receptor activator for nuclear factor-κB ligand; TCR, T-cell receptor; TNFR, tumor necrosis factor receptor; VLA, very late antigen.

Figure 2

Cell contact-dependent effector function. Spatial and temporal organization of synovial inflammatory infiltrates favor cell contact-dependent effector responses between T cells, B cells, macrophages, and resident stromal cells and adipocytes. The extent to which Tregs influence these effector pathways is presently unclear. ADAM, a disintegrin and metalloprotease; ADAM TS, ADAM with ThromboSpondin-like motifs; FLS, fibroblast-like synoviocytes; GM-CSF, granulocyte macrophage colony-stimulating factor; HMGB1, high-mobility group box-1 proteins; IL, interleukin; M-CSF, macrophage colony-stimulating factor; MΦ, macrophage; MMP, matrix metalloproteinase; PG, prostaglandin; RANKL, receptor activator for nuclear factor-κB ligand; TCR, T-cell receptor; Teff, effector T cell; TNF, tumor necrosis factor; Treg, T regulatory cell; VEGF, vascular endothelial growth factor.

Figure 3

Pathway biology: the impact of RA-associated allelic variants. Multiple single nucleotide polymorphisms may contribute to the disease-prone state through subtle modifications in antigen presentation ('single input') and T-cell antigen receptor responsiveness ('signal output'). It is proposed that these variants may influence multiple pathways of T-cell activation, differentiation, and effector function. DC, dendritic cell; RA, rheumatoid arthritis; TCR, T-cell receptor; T_eff, effector T cell; Th, T-helper cell.