TIM-1 defines a human regulatory B cell population that is altered in frequency and function in systemic sclerosis patients

Octavio Aravena, Ashley Ferrier, Madhvi Menon, Claudia Mauri, Juan Carlos Aguillón, Lilian Soto, Diego Catalán

Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by excessive production of extracellular matrix by fibroblasts on skin and internal organs. Although Th2 cells have been involved in fibroblast stimulation, hyperactivated B cells may also play an important role. Regulatory B cells (Bregs) are cells capable of inhibiting inflammatory responses and controlling autoimmune diseases. Although many Breg populations have in common the ability to produce high amounts of IL-10, a unique surface marker defining most human Bregs is lacking. It has been described in mice that T cell Ig and mucin domain protein 1 (TIM-1) is an inclusive marker for Bregs, and that TIM-1+ B cells are able to prevent the development of autoimmunity. The aim of this work was to evaluate TIM-1 as a marker for human IL-10(+) Bregs, and to determine whether TIM-1+ B cells are defective in SSc patients. SSc patients (n = 39) and 53 healthy subjects were recruited. TIM-1 and IL-10 expression was assessed in resting or activated peripheral blood CD19(+) B cells by flow cytometry. The regulatory function of TIM-1(+) or activated B cells from SSc patients and healthy subjects was assessed in autologous and allogenic co-cultures with CD4(+) T cells, where T cell proliferation and IFN-γ, IL-17, TNF-α and IL-4 production by T cells was measured by flow cytometry. TIM-1 and IL-10 were preferentially expressed in transitional B cells, but were upregulated in naïve and memory B cells upon stimulation. The frequency of transitional TIM-1(+) IL-10(+) B cells was significantly decreased in SSc patients compared to healthy controls. In addition, activated B cells from SSc patients induced stronger allogenic Th1 and Th2 responses than activated B cells from healthy controls. Finally, TIM-1(+) B cells, including transitional and non-transitional cells, exhibited a higher CD4(+) T cell suppressive ability than TIM-1(-) B cells in healthy controls, but not in SSc patients. TIM-1 is a unique marker for the identification of a human IL-10(+) Breg subpopulation which is partially superimposed with transitional B cells. Alterations in TIM-1(+) B cells could contribute to the development of autoimmune diseases such as SSc.