SLE T cells express higher levels of CD44, a surface adhesion molecule, and in vitro show stronger adhesion and faster migration in response to chemokines. CD44 occurs as a number of different isoforms; the distinct functions and characteristics of these variants are unclear. SLE T cells express higher levels of the CD44v3 and CD44v6 in particular, and this pattern of adhesion molecule expression is also seen in T cells infiltrating the kidneys of patients with lupus nephritis.14 CD44v3 (but not CD44v6) also has been implicated in the T-cell infiltrates of autoimmune skin conditions, including those associated with lupus. Within the cell, CD44 signals through its association with ezrin, radixin, and moesin (collectively known as ERM). Upon activation of CD44, the ERM signaling molecules are phosphorylated by rho kinase (ROCK); ERM proteins show higher levels of phosphorylation in patients with lupus.11 Suppression of the CD44 activation pathway by silencing CD44 expression or inhibiting ROCK normalizes the enhanced migratory responses of SLE T cells and may therefore have therapeutic applications. ROCK inhibitors have been shown to have other antiinflammatory effects as well, including inhibition of IL-17 and other inflammatory cytokines in mouse models of autoimmunity.15 (See Figure 2)
Th17 and Double-Negative T Cells
Th17 cells are a subset of T helper cells that produce IL-17. This cell type has been shown to play a role in a number of autoimmune diseases, including multiple sclerosis and inflammatory bowel disease. T cells secreting IL-17 have also been found in increased numbers in patients with SLE, including in the kidneys of patients with lupus nephritis. The production of IL-17 is thought to amplify the local inflammatory response by stimulating the recruitment other immune effector cells. Antibodies inhibiting the IL-17 pathway are already being evaluated for the treatment of rheumatoid arthritis; it remains to be seen whether anti–IL-17 strategies will also be useful for treating SLE.16
Under normal circumstances, almost all circulating T cells will express either CD4 or CD8 surface markers. A subpopulation of CD4–, CD8–(double-negative, or DN) T cells have also been described, although their function is not completely clear. DN T cells appear to have regulatory properties as they can suppress other T-cell responses. However, the DN T-cell population is also expanded in some autoimmune conditions. In SLE, DN T cells play an inflammatory role and can be found producing IL-17 within the kidneys of patients with lupus nephritis.17 Local infiltration of T cells and other inflammatory cells into the kidneys suggests that secreted cytokines and chemokines may be detectable in the urine. A change in cytokine profile in the urine may precede the development of renal damage and could therefore serve as a biomarker predictive of renal involvement.18
