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

Abstract

BackgroundSystemic 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.MethodsSSc 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.ResultsTIM-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.ConclusionsTIM-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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1213-9) contains supplementary material, which is available to authorized users.

Regulatory B cells and advances in transplantation

“…19 In healthy controls, TIM-1 + B cells, including nontransitional and transitional cells, more effectively suppress CD4 + T cells than do TIM-1 − B cells. 120 The above-mentioned results suggest TIM-1, which probably defines a human Breg population, as a potential target for treatment in the transplantation field. 121…”

“…In HIV‐infected patients, TIM‐1 has been used as a surface marker to isolate Bregs, thereby facilitating the study of their regulatory activities in vitro . In healthy controls, TIM‐1 + B cells, including nontransitional and transitional cells, more effectively suppress CD4 + T cells than do TIM‐1 − B cells . The above‐mentioned results suggest TIM‐1, which probably defines a human Breg population, as a potential target for treatment in the transplantation field …”

Altered frequency of CD24highCD38high transitional B cells in patients with cardiac involvement of chronic Chagas disease

“…Several subsets of IL-10 producing B cells have been described in humans, their definition depending on the disease under study, the immunological context and the stimulation conditions. These include CD1d + CD5 + (43,44), Tim-1 + (15,16), immature transitional CD24 hi CD38 hi (11,41) and memory CD24 high CD27 + B cells (12).…”

“…However, and due to the absence of subset-specific membrane markers or transcription factors, IL-10 secretion is still the hallmark feature used to distinguish Breg from the rest of the B cells (9,10). In humans, different B cell lineages that secrete this cytokine and have regulatory functions have been described, such as CD19 + CD24 high CD38 high (11), CD19 + CD24 high CD27 + (12), CD19 + CD5 + CD1d + (13,14), CD19 + Tim-1 + (15,16) and CD19 + CD25 + CD71 + CD73cells (7), depending on the stimulation conditions and the markers used to identify them. Nowadays, the majority of the studies in human samples pinpoint the CD19 + CD24 high CD38 high immature transitional B cell population as the most representative phenotypic signature of Breg cells (17).…”

Regulatory B cells: Development, phenotypes, functions, and role in transplantation

“…[15][16][17] Although mouse and human Bregs lack a common phenotype, some shared phenotypic markers have been identified and different subsets have been documented. 21,23 In human, several B-cell subsets have also been reported to be regulatory, including transitional B cells CD24 hi CD38 hi , 2,25-28 CD19 + CD24 hi CD27 + B10 cells, [29][30][31] plasmablast CD27 inter CD38 + , 24 Tim-1 + Bregs, 32 and CD25 + CD71 + B regulatory 1. 21,23 In human, several B-cell subsets have also been reported to be regulatory, including transitional B cells CD24 hi CD38 hi , 2,25-28 CD19 + CD24 hi CD27 + B10 cells, [29][30][31] plasmablast CD27 inter CD38 + , 24 Tim-1 + Bregs, 32 and CD25 + CD71 + B regulatory 1.…”