Abstract
BXD2 mice spontaneously develop autoantibodies and subsequent glomerulonephritis, offering a useful animal model to study autoimmune lupus. Although initial studies showed a critical contribution of IL-17 and Th17 cells in mediating autoimmune B cell responses in BXD2 mice, the role of follicular helper T (Tfh) cells remains incompletely understood. We found that both the frequency of Th17 cells and the levels of IL-17 in circulation in BXD2 mice were comparable to those of wild-type. By contrast, the frequency of PD-1+CXCR5+ Tfh cells was significantly increased in BXD2 mice compared with wild-type mice, while the frequency of PD-1+CXCR5+Foxp3+ follicular regulatory T (Tfr) cells was reduced in the former group. The frequency of Tfh cells rather than that of Th17 cells was positively correlated with the frequency of germinal center B cells as well as the levels of autoantibodies to dsDNA. More importantly, CXCR5+ CD4+ T cells isolated from BXD2 mice induced the production of IgG from naïve B cells in an IL-21-dependent manner, while CCR6+ CD4+ T cells failed to do so. These results together demonstrate that Tfh cells rather than Th17 cells contribute to the autoimmune germinal center reactions in BXD2 mice.
Highlights
CD4+ T cells provide ‘help’ to B cells by inducing somatic hypermutation, class-switching and the differentiation into memory B cells or long-lived plasma cells (PC) during germinal center (GC) reactions [1]
As a first step to determine the contribution of each T helper (Th) cell response to autoimmune lupus in BXD2 mice, we comparatively analyzed the production of autoantibodies and the generation of spontaneous germinal center reactions between BXD2 mice and C57BL/6 control mice at the age of 6 months or older
We observed spontaneous generation of GCs in the BXD2 mice (Fig. 1B and 1C), which was associated with increased frequency and number of GL7+Fas+ germinal center B cells in the spleens (Fig. 1D)
Summary
CD4+ T cells provide ‘help’ to B cells by inducing somatic hypermutation, class-switching and the differentiation into memory B cells or long-lived plasma cells (PC) during germinal center (GC) reactions [1]. CXCR5+ICOS+PD-1+ follicular T helper (Tfh) cells have recently been shown to play crucial roles in promoting GC reactions [2] by providing IL-21and ICOS costimulation which are important for the above described germinal center B cell responses, as well as for the clonal expansion of antigen-specific B cells [3,4,5,6,7,8,9]. Tfh cell responses are essential for the generation of effective humoral responses against invasion of infectious agents. Excessive Tfh cell responses to self-antigens are shown to be PLOS ONE | DOI:10.1371/journal.pone.0120294. Excessive Tfh cell responses to self-antigens are shown to be PLOS ONE | DOI:10.1371/journal.pone.0120294 March 13, 2015
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