This contributes to disease pathology, in part via positive feedback loops between T and myeloid cells [49, 50]. The percentage of CD4+ cells expressing the

activation marker CD69 was elevated compared with that in WT in lyn–/–, but not lyn–/–IL-21–/– mice (Fig. 6C and Supporting Information Fig. 4). However, the frequency of IFN-γ, IL-4, and IL-17-producing cells among CD4+ T cells was similar in aged lyn–/– and lyn–/–IL-21–/– mice (Fig. 8D, Supporting Information Fig. 4). In the myeloid compartment, we observed an elevated frequency of CD11b+ cells in both lyn–/– and lyn–/–IL-21–/– spleens (Fig. 7). This increase was primarily in the CD11b+Gr1+CD11c− subset (Fig. 7). Because of variability in the total number of splenocytes in aged lyn–/– and lyn–/–IL-21–/– mice (Supporting Information Fig. 5), it was difficult to detect significant changes in the total number of T and myeloid cell subpopulations. buy Acalabrutinib However, since the relative frequency of myeloid cells is increased significantly in both lyn–/– and lyn–/–IL-21–/– mice, other cell types will have greater exposure to them and the factors they produce than in WT mice. Finally, we asked whether IL-21 mediates kidney damage in lyn–/– mice. Despite the lack of anti-DNA IgG, aged lyn–/–IL-21–/– mice experienced severe GN (Fig. 8A and B). They also demonstrated an increased frequency of CD11b+ (both CD11c−/lo and CD11c+ subsets) and CD8+ cells in the

kidneys (Fig. 8C RXDX-106 and Supporting Information Fig. 6). Each of these populations has been shown to be elevated in the nephritic kidneys of other lupus models [51, 52]. IgG deposits were observed in four of four lyn–/–IL-21–/– kidneys examined (Fig. 8B and Supporting Information Fig. 6), likely due to residual autoreactive IgG against non-DNA Ags (Fig. 5). Tubular interstitial nephritis was minimal, although mildly elevated (Supporting Information Fig. 6). These results are consistent with a predominant role for immune complex-mediated

kidney damage. IL-21 is associated with lupus in both humans and mice [18, 29-36]. While IL-21 mRNA is not significantly elevated in Lyn-deficient mice, several manipulations that reduce autoantibodies also dampen IL-21 expression. This suggested a role for IL-21 in the autoimmune phenotype of lyn–/– mice. Indeed, we show that IL-21 is required for IgG against Epothilone B (EPO906, Patupilone) DNA and some other, but not all, self-Ags in lyn–/– mice. However, IL-21 is dispensable for kidney damage in these animals. IL-21 could promote autoreactive B-cell class switching in two ways; by directly acting on B cells [18, 19, 21, 25-28], and/or by maintaining ICOS+CXCR5− and ICOS+CXCR5+ CD4+ T cells. These subsets are efficient B-cell helpers in extrafollicular and GC responses, respectively [29, 30]. Autoreactive B cells are likely activated in an extrafollicular response in lyn–/– mice. These animals fail to form GCs, either spontaneously or in response to immunization [4, 47, 48].