B Cell: T Cell Interactions Occur within Hepatic Granulomas during Experimental Visceral Leishmaniasis

Abstract

Hepatic resistance to Leishmania donovani infection in mice is associated with the development of granulomas, in which a variety of lymphoid and non-lymphoid populations accumulate. Although previous studies have identified B cells in hepatic granulomas and functional studies in B cell-deficient mice have suggested a role for B cells in the control of experimental visceral leishmaniasis, little is known about the behaviour of B cells in the granuloma microenvironment. Here, we first compared the hepatic B cell population in infected mice, where ≈60% of B cells are located within granulomas, with that of naïve mice. In infected mice, there was a small increase in mIgM lo mIgD + mature B2 cells, but no enrichment of B cells with regulatory phenotype or function compared to the naïve hepatic B cell population, as assessed by CD1d and CD5 expression and by IL-10 production. Using 2-photon microscopy to quantify the entire intra-granuloma B cell population, in conjunction with the adoptive transfer of polyclonal and HEL-specific BCR-transgenic B cells isolated from L. donovani -infected mice, we demonstrated that B cells accumulate in granulomas over time in an antigen-independent manner. Intra-vital dynamic imaging was used to demonstrate that within the polyclonal B cell population obtained from L. donovani -infected mice, the frequency of B cells that made multiple long contacts with endogenous T cells was greater than that observed using HEL-specific B cells obtained from the same inflammatory environment. These data indicate, therefore, that a subset of this polyclonal B cell population is capable of making cognate interactions with T cells within this unique environment, and provide the first insights into the dynamics of B cells within an inflammatory site.

Rapid activation and hepatic recruitment of innate-like regulatory B cells after invariant NKT cell stimulation in mice

“…Inflammation suppressing effects of innate-like B cells have classically been associated with their ability to produce IL-10 [13,15,17]. We confirm the presence of IL-10 producing B cells in mouse liver [22], and demonstrate a significant increase in hepatic IL-10 + B cells post-αGalCer treatment (Fig. 5A,B).…”

“…Major B cell subsets recruited into the liver after iNKT cell activation were phenotyped using flow cytometry. B1 B cell subsets (B1a and B1b) were identified based on cell surface expression of B220 and CD5 [20][21][22]. MZ and FO B cell subsets were characterized based on differential CD21 and CD23 expression [23,24] The spleen is the major source of MZ-like B cells, and the peritoneal cavity is the major source of B1 B cells, recruited into the liver after αGalCer treatment.…”

Emerging Trends in the Formation and Function of Tuberculosis Granulomas

“…In recent years, multiple studies suggest an immune-modulatory role for B-cells in T-cell activity at the granuloma level. On one hand, B-cells can co-localize with T-cells in TB granulomas (Ulrichs et al, 2004; Beytut, 2011), and directly interact with them in the granulomas caused by Leishmania (Moore et al, 2012). On the other hand, B-cells influence T-cell effector functions either through cytokine production or antigen-presentation (Lund and Randall, 2010).…”

Liver metastases induce reversible hepatic B cell dysfunction mediated by Gr-1+CD11b+ myeloid cells

“…Although HBC represent a large proportion of liver lymphocytes and interact with hepatic T cells [11,12], their role in the LM environment remains virtually unexplored. Murine data regarding the role of B cells in cancer is complex, demonstrating that B cells inhibit anti-tumor responses in some models, while enhancing tumor protection in others [13][14][15][16][17][18][19].…”

“…To date, we have a limited understanding of how HBC may impact the biology of liver tumors. The function of intrahepatic immune cells compared with their counterparts in other sites is often distinct [3,11,12,22]. Therefore, an investigation of how HBC function is affected by liver tumors is warranted.…”